Dopamine D3 Receptor Partial Agonists and Antagonists as

© Copyright 2005 by the American Chemical Society

Volume 48, Number 11

June 2, 2005

Perspective Dopamine D3 Receptor Partial Agonists and Antagonists as Potential Drug Abuse Therapeutic Agents Amy Hauck Newman,*,† Peter Grundt,† and Michael A. Nader‡ Medicinal Chemistry Section, National Institute on Drug AbusesIntramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, and Departments of Physiology/Pharmacology & Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083 Received October 26, 2004

1. Introduction The stimulation of dopamine receptors via an increased concentration of synaptic dopamine levels in the mesocorticolimbic regions of the brain has been defined as the primary mechanism underlying the reinforcing properties of all drugs of abuse. As such, most of these substances do not directly bind to dopamine receptors, but rather, their actions are mediated through indirect mechanisms such as dopamine transporter blockade (e.g., cocaine). The resulting increases in synaptic dopamine levels in turn produce euphoria, psychostimulation, and other rewarding experiences that can lead to drug addiction. Indeed, imaging studies in drugaddicted subjects have shown increases in dopamine levels in striatal regions of the brain after cocaine administration,1 and these subjects show marked dopaminergic dysfunction highlighted by decreases in dopamine release and D2 receptors that have been associated with both impulsive and compulsive behaviors.2 Studies of reward neurocircuitry and brain adaptations that result from both acute and chronic drug use have been the topic of intensive investigation3-5 and have revealed that simple stimulation of dopamine receptors to produce pleasure is certainly an initiating factor in drug abuse but is a profound simplification of the subsequent addiction process.6,7 Understanding the role and function of each dopamine receptor subtype, its neuroana* To whom correspondence should be addressed. Phone: (410) 5506568, extension 114. Fax: (410) 550-6855. E-mail: anewman@ intra.nida.nih.gov. † National Institute on Drug Abuse-Intramural Research Program. ‡ Wake Forest University School of Medicine.

tomical location and ultimate neuroadaptive modifications, as a result of both acute and chronic drug taking is paramount to developing treatment strategies for drug addiction.8,9 Presently, the individual roles of the dopamine receptor subtypes in both reward and the addiction process remain unclear in part because of the lack of highly selective pharmacologic tools with which to study these receptors in vivo. Currently, cocaine remains the major drug of abuse for which there is no pharmacological treatment available. The abuse of cocaine has been a persistent health and social problem worldwide and affects more than 2 million people in the U.S. alone.10 Intensive investigation and development of animal models of cocaine abuse have resulted in numerous preclinical avenues with which to evaluate potential cocaine abuse medication. However, the lack of even one comparative standard (e.g., methadone for heroin abuse) has led some researchers to question the validity of these models to the uniquely human condition of cocaine abuse.11 Currently, the most commonly used animal models to evaluate dopaminergic compounds as potential medications for cocaine abuse are locomotor stimulation, cocaine drug discrimination, self-administration, and a number of reinstatement models of drug seeking or craving in rodents and nonhuman primates.12,13 The combination of two or more of these models, coupled with extensive in vitro evaluation of potential leads for cocaine-abuse medications, has been the strategy of numerous researchers to both identify candidates for clinical development and, further, elucidate mechanistic correlates of their effectiveness.14,15

10.1021/jm040190e CCC: $30.25 © 2005 American Chemical Society Published on Web 04/21/2005

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Figure 1. Representative first-generation D3 selective antagonists/partial agonists.

From the pharmacological perspective, two approaches toward cocaine abuse treatment have been pursued. The substitute-therapy approach provides a medication that would have pharmacological similarity to cocaine (e.g., direct or indirect dopamine receptor agonist) and would potentially assist a cocaine addict in not seeking cocaine during abstinence because of the anhedonia and other negative effects resulting from modified dopamine levels.16 By manipulation of the pharmacokinetics of these agents to have a slow onset and long duration of action, their own addictive liability may be decreased and dosing convenience as well as promotion of compliance might be achieved.12,17 The second approach is pharmacological antagonism wherein a dopamine receptor antagonist or partial agonist would attenuate dopamine receptor stimulation because of increased levels of dopamine and thus would theoretically reduce the pleasurable feelings normally afforded by cocaine through this mechanism.18 Although the antagonist approach has had limited success for other drug addictions (e.g., naltrexone for opiate addiction), the partial agonist approach has demonstrated success (e.g., buprenorphine for opiate addicts), and both remain viable avenues for cocaine abuse. The selective antagonism of a dopamine receptor subtype might afford the desired inhibition of cocaine’s effects without also producing undesirable side effects.12 The five known mammalian dopamine receptor subtypes (D1-D5), which, on the basis of protein homology and function,19 can be divided into two receptor families, D1-like (D1 and D5) and D2-like (D2, D3, and D4), are all G-protein-coupled receptors (GPCR). The D3 receptor subtype was first cloned and characterized by Sokoloff and colleagues and reported in 1990.20 This discovery led to an explosion of investigation including the transfection of cell lines with the cloned D2-like receptor subtypes for binding and in vitro functional tests21 and the development of mutagenic mice with the deletion of dopamine D3 receptors for behavioral investigation.22-26 Likewise, a scramble toward the identification of structure-activity relationships (SAR) at the dopamine D3 receptor that would enable the discovery and development of novel and selective dopamine D3 receptor agonists and antagonists for pharmacological study ensued.27,28 It has been well established that nonselective dopamine receptor agonists and antagonists would have limited therapeutic utility as cocaine abuse medications because of their untoward side effects.29 Specifically, dopaminergic agonists, although admittedly non-

selective, have not shown promise in clinical trials for drug abuse.30 Moreover, discovering a selective pharmacophore for the dopamine D3 receptor with full intrinsic activity has thus far remained elusive. Therefore, this report will limit its discussion of potential dopamine D3 receptor agents, currently being developed as medications for drug abuse and other neuropsychiatric disorders, to partial agonists and antagonists. 2. Dopamine D3 Receptor Partial Agonists and Antagonists Pharmacological investigation of receptors, in general and the dopamine receptor subtypes specifically, has been traditionally led by the discovery of small molecules that are designed to bind with high affinity and selectivity to these receptor proteins. With the development of radioligand displacement assays and by means of cloned receptors that can be transfected into stable cell lines, rapid and efficient determination of binding affinities at the various dopamine receptor subtypes can be assessed. Additionally, in vitro assays such as agonist-stimulated mitogenesis or the inhibition of quinpirole-stimulated mitogenesis for identifying functional antagonists at the various receptor subtypes have allowed for quick determination of efficacy and provided data to predict an agonist, partial agonist, or antagonist profile at the various D2-like receptors in vivo. Using classically and/or computationally derived drug design and synthesis, thousands of novel ligands have been investigated for their D3 receptor binding affinities, selectivities, and intrinsic activities. The history of these ligands and a thorough examination of D3 SAR have recently been reviewed.27,28 For the purpose of this perspective, four representative ligands that demonstrate both high affinity and selectivity for the D3 receptor and for which in vitro and in vivo pharmacology directed toward the development of potential medications has been investigated and reported will be discussed (Figure 1). Second- and third-generation D3 ligands that have been reported and are in earlier stages of development will then be described, and SAR will be provided for optimized D3 receptor affinity and selectivity and in vivo study. Where these compounds have been evaluated in vitro in differing assays and/or in different labs, the results will be compared. (Note that selectivity ratios throughout this paper will be expressed as D2/ D3, a ratio that is derived from the Ki value at D2 over the Ki value at D3 receptors. Hence, a compound that exhibits higher affinity at D3 than at D2 receptors has

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a D2/D3 ratio greater than 1. Ideally, this ratio should be >100 for demonstration of in vivo selectivity.) 2.1. BP 897. BP 897 (1) was first identified in a French drug discovery program and disclosed in a European patent (EP0779284)31 as a dopamine D3 receptor partial agonist with potential for the treatment of Parkinson’s disease and neuropsychiatric disorders such as depression and drug addiction.32 In 1999, BP 897 (1) was reported as a selective dopamine D3 receptor partial agonist.33 It exhibited high-affinity binding at D3 (Ki ) 0.92 nM) and 70-fold selectivity over D2 receptors (Ki ) 61 nM) while also demonstrating moderate selectivity over the D1, D4, R1, and R2, 5HT1A, and 5HT7 receptors and high selectivity over the muscarinic, histaminic, and opioid receptors.33 BP 897 (1) potently increased mitogenesis in NG 108-15 cells expressing human D3 receptors (EC50 ) 3 nM) but at a maximum efficacy of 55% and hence was described as a D3 partial agonist. Numerous other in vitro and in vivo tests of D3 receptor occupancy and intrinsic activity were assessed, which led these investigators to further evaluate this novel agent in several animal models of cocaine seeking. In this initial study, rats were trained under a schedule in which drug seeking was maintained by cues associated with cocaine. BP 897 (1) decreased drug seeking.33 However, when cocaine was available under a continuous reinforcement schedule, BP 897 (1) did not affect self-administration, suggesting that it was selectively affecting drug-associated cues. When substituted for cocaine, BP 897 (1) did not have reinforcing effects. This behavioral profile was attributed to BP 897 (1) being a partial agonist at D3 receptors in vivo, wherein it was speculated to block reward circuitry initiated by increases in dopamine levels but maintain a low-level of dopamine receptor stimulation.33 The latter finding has been confirmed in models of conditioned locomotor activity,34,35 conditioned place preference (CPP),36 and cocaine-cue reinstatement.37,38 Furthermore, BP 897 (1) did not have cocaine-like discriminative stimulus effects in mice nor did it function as a reinforcer in rhesus monkeys.39 These studies will be discussed in more detail in section 6. Subsequently, two reports appeared wherein the efficacy of BP 897 (1) was further evaluated in additional in vitro models. Using microphysiometry to measure agonist-induced extracellular acidification rates in hD2L and hD3 receptors expressed in Chinese hamster ovary (CHO) cells, BP 897 (1) showed no increases in acidification whereas the classic D2/D3 agonist quinpirole showed a dose-related stimulation.40 Further, BP 897 (1) dose-dependently shifted the quinpirole dose-response curve to the right, supporting its characterization as an antagonist at both D2L and D3 receptors.40 In the second study, dopamine and the D2/ D3 agonists R-(+)-7-OH DPAT, PD 128907, and quinpirole dose-dependently increased [35S]GTPγS binding to membranes of hD3 receptors expressed in CHO cells.41 However, BP 897 (1) failed to induce this increase and attenuated the effect of dopamine, leading these investigators to characterize it as a D3 antagonist as well.41 In addition, the in vivo effect of BP 897 (1) in the rat substantia nigra was evaluated where it showed no effect on dopaminergic firing. In contrast, dopamine

and the dopamine agonists R-(+)-7-OH DPAT, PD 128907, and quinpirole showed dose-dependent inhibition of firing. BP 897 (1) antagonized the quinpiroleinduced inhibition of firing rate, as did the classic nonselective D2 receptor antagonists haloperidol and clozapine.41 In combination, these data suggested that BP 897 (1) might act as an antagonist rather than a partial agonist at dopamine D3 receptors in vivo. This conclusion is further supported by the similar behavioral profiles of dopamine D3 receptor antagonists in animal models of drug abuse (see section 6). 2.2. SB 277011. SB 277011 (2) was developed in a large synthetic program at GlaxoSmithKline (formerly SmithKline Beecham) in which a pharmacophore for potent and selective D3 receptor antagonist activity had already been established. Chemical modifications were made not only to optimize the pharmacological specificity of these ligands but also to improve bioavailability for in vivo testing. Previous investigations had already established that in order to obtain high affinity and D3 selectivity, the resulting molecules had to be large and lipophilic, negatively impacting pharmacokinetics and bioavailability and thus reducing their usefulness as in vivo probes.42,43 Stemp and colleagues reasoned that structural rigidity in the butyl linker between the amide function and the azacyclic terminus would improve D3 selectivity over serotonin receptor subtypes.42 Further, incorporating heteroatoms into the required aryl terminus and adding the cyano substitution served to reduce lipophilicity and improve oral bioavailability. Using a parallel synthesis approach, these efforts resulted in SB 277011 (2).42 Initial in vitro evaluation showed SB 277011 (2) to have high D3 receptor affinity (pKi ) 8.0; Ki ) 10 nM) and >100-fold selectivity over D2, 5HT1B and 5HT1D receptors. By use of microphysiometry in hD3 receptors expressed in CHO cells, SB 277011 (2) was devoid of agonist actions and was 100fold selective over D2 as a D3 receptor antagonist. Further, SB 277011 (2) dose-dependently reversed the effects of the dopamine agonist quinelorane on dopamine firing in rat nucleus accumbens, demonstrating its D3 antagonist profile in vivo.42 Numerous studies investigating SB 277011 (2) in models of substance abuse have been reported and will be highlighted in section 6. 2.3. S33084. S33084 (3) was first described as the most potent and selective D3 antagonist in a series of analogues reported by Servier Institute of Research, wherein a biphenylbutylamide was linked to a cyanosubstituted benzopyrano[3,4-c]pyrrole system.44 Determined by its ability to displace [125I]iodosulpiride from hD3 receptors in CHO cells, as with SB 277011 (2), S33084 (3) showed high binding affinity for the D3 receptor (pKi ) 8.6 nM) and was 120-fold selective over the hD2 receptor.44 It also demonstrated an antagonist profile in [35S]GTPγS binding at both hD3 and hD2 receptors44 with ∼30-fold D3 selectivity ratio. Further pharmacological characterization and comparison to the less selective D3 antagonist GR218,231 and the D2selective antagonist L741,626 extended these findings and showed S33084 (3) to be >100-fold selective for D3 in over 20 additional central receptor systems.45 Further characterization in additional in vitro and in vivo assays

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of dopaminergic function, as described for BP 897 (1) and SB 277011 (2), clearly defined S33084 (3) as a potent, competitive, and D3-selective antagonist.46 This compound has been tritiated and used for further characterization of dopamine D3 receptors.47 2.4. NGB 2904. As part of Neurogen’s synthetic program directed toward the dopamine D2-like receptor family subtypes D3 and D4, the 9H-fluorenyl analogue NGB 2904 (4) and its biphenylene derivative were discovered as leads for novel antipsychotic medications. The investigators reasoned that because D3 receptors appeared to have different G-protein coupling mechanisms compared with D2 receptors, these differences might be associated with the behavioral expression of schizophrenia. As such, dopamine D3 receptor antagonists might serve as a reasonable and novel target for treatment of schizophrenia and other neuropsychiatric disorders.48 Compared to BP 897 (1), NGB 2904 (4) shared the characteristic butylamide linking chain and an extended aromatic terminus on one end and differs by a 2,3-dichlorophenylpiperazine on the other. This compound and its biphenylene analogue demonstrated high binding affinities at the hD3 receptor (1.4 and 0.9 nM, respectively) and >150-fold selectivity over the D2 receptor as measured by displacement of [3H]YM-091512 from primate D2L or D3 receptors expressed in CHO cells.48 In addition, these compounds were >100-fold selective over R1 and 5HT2 receptors and >1000-fold selective in a 60-receptor Panlabs screen, with NGB 2904 (4) having a slightly better selectivity profile.48 Neither compound stimulated D3-receptor-mediated [3H]thymidine uptake in CHO cells. NGB 2904 (4), like haloperidol, antagonized 100 nM quinpirole-stimulated mitogenesis with an IC50 value of 5.0 nM.48 Shortly after this publication, Neurogen terminated its synthetic program on D3 ligands49 and we (A.H.N.) began a synthetic program directed toward optimizing D3 receptor affinity, selectivity, and bioavailability of compounds based on the parent structure of NGB 2904 (4). Although the preliminary in vitro profile of NGB 2904 (4) looked promising, no in vivo data were in the public domain, and we suspected that this compound might have limited bioavailability and poor pharmacokinetics because of its high lipophilicity. Hence, synthesis of NGB 2904 (4) for further biological characterization was followed by a drug design strategy to further improve the pharmacological profile of this compound, to develop SAR around the parent structure, and ultimately to discover novel D3 ligands that could be useful for in vivo investigation.50-52 By examination of the pharmacokinetic profile of NGB 2904 (4) in rats, preliminary studies recently showed a moderate distribution volume and a high blood clearance (74% of rat liver blood flow) after a single iv injection of 0.5 mg/kg. The mean brain-toblood ratio for this compound was 1.7, but absolute brain levels were significantly lower (62 ng/g) than those obtained for SB 277011 (2) under the same conditions.53

brief, low nanomolar to subnanomolar D3 affinity is achieved when either a saturated butylamide or a cyclohexylethyl amide possessed an extended aromatic ring system such as a fluorenyl or biphenylene on one terminus and an azacyclic ring system, such as a phenylpiperazine [BP 897 (1) or NGB 2904 (4)] or structurally more rigid isostere, on the other [SB 277011 (2) or S33084 (3)]. Although replacement of the amide function with other linking atoms has been reported, the amide function appears to be optimal.27 Reducing or increasing the linking chain by a simple methylene group significantly decreased D3 binding affinity and/ or selectivity,50,54 and decreasing the size of the terminal aromatic ring also served to reduce the affinity and selectivity for D3 receptors.50,51 Likewise, only specific substitutions on the phenylpiperazine were well-tolerated at D3 receptors, such as 2,3-dichloro or 2-methoxy substituents, and significant reductions in D3 receptor affinity resulted when this substitution pattern was modified,27,31,50 although there have been reports of other phenyl substitutions that were well-tolerated at D3 receptors.37 Moreover, optimized bioavailability was obtained with a cyano substitution on the termini of SB 277011 (2) and S33084 (3). On the basis of these SAR, numerous papers have been published in the past 3-4 years describing novel but structurally related D3selective antagonists and partial agonists, and several of these ligands represent the future in vivo tools for D3 receptor investigation (Figure 2). Those reports that highlight D3-selective antagonists or partial agonists as potential in vivo probes will be described in section 6. In an effort to identify novel D3 receptor pharmacophores, simple chemical modification of the parent NGB 2904 (4) was undertaken to identify optimal linking chain length, phenylpiperazine substitution, and fluorenyl ring position substitution.50 SAR in this study confirmed the optimal butylamide linking chain and established that the 2,3-dichloro-substituted phenylpiperazine gave higher D3 receptor binding affinity than the monochloro-substituted or unsubstituted phenyl ring and that the optimal fluorenyl substitutions were at positions 2 and 4. The analogue with the highest affinity and selectivity for D3 in this study was compound 5, which was equipotent to NGB 2904 (4) at D3 receptors but slightly more potent at D2, resulting in a 64-fold selectivity vs 155-fold D2/D3 selectivity for NGB 2904 (4).50 These SAR were confirmed and expanded upon by the Gmeiner group who reported that the naphthyl group of BP 897 (1) could be replaced with heteroatom substituted bicyclic ring systems, resulting, after introduction of a 2,3-dichloro substitution on the phenylpiperazine moiety, in their most hD2/hD3-selective (7200fold) benzo[b]thiophene analogue, 6.54 Although the hD3 affinity of this compound (Ki ) 0.5 nM) was in the subnanomolar range of affinities that several analogues reported in this paper and by others had achieved with closely related analogues, the hD2L receptor affinity under the assay conditions employed was notably low (Ki ) 3600), rendering the extraordinarily high selectivity for D3 over D2 receptors. However, around the same time, analogue 6 was reported by another group to display significantly higher affinity at hD2L receptors (Ki ) 170 nM) than was reported by the Gmeiner

3. Next Generation of D3-Selective Antagonists/ Partial Agonists as In Vivo Probes The SAR that have been derived from the laboratories in which these four D3 compounds were synthesized have provided the basis for the next generation of D3selective ligands to be used for in vivo investigation. In

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Figure 2. Highlighted second-generation D3-selective antagonists/partial agonists.

group.55 In this second report, the more D3-selective ligand was the benzofuranyl derivative 7, also prepared by the Gmeiner group. However, it was noted that Leopoldo et al. compared binding affinities at rat D3 with human D2 receptors and that significant differences in binding affinities across species have been reported.51 Further elaboration on the discrepancies in binding affinities/selectivities across laboratories will be discussed in section 4.1. Another report appeared in 2003 in which additional heterocyclic analogues of BP 897 (1) were described.37 In that article, the 2-methoxy-substituted phenylpiperazine was retained and various heterocyclic replacements of the naphthyl ring were explored. Subsequently, replacement of the 2-methoxy group with 3,4-dichloro, 2,4-dichloro, and 4-cyano groups was investigated. Although these authors report the discovery of several highly selective D3 ligands, compared to the parent ligand BP 897 (1), the binding assays employed were significantly different. For example, for D3 receptor binding, [3H]7-OH DPAT was displaced from rat D3 receptors in Sf9 cells, whereas the nonselective D2 receptor antagonist [3H]spiperone was displaced from rat striatum for D2 receptor binding. Thus, the indolering-substituted analogues with the 2,4-dichlorophenylpiperazine ring were reported to be highly selective D3 receptor antagonist, and behavioral evaluation was not consistent with that reported for other compounds, such as SB 277011 (2), with this in vitro profile.37 A report in 2003 came from the Stark group in which further elaboration on the BP 897 (1) structure was undertaken. In this study, the 2-methoxy-substituted phenylpiperazine moiety was retained, but the linking amide chain and the terminal aromatic ring system were modified.56 In a second series of compounds, designed in part from molecular models, a styrene structure replaced the naphthalene ring system of BP 897 (1). The terminal iodo-substituted derivative 8 showed high affinity (Ki < 0.5 nM) and selectivity (>150fold) for D3 over D2 receptors.56 On the basis of this

binding profile, it was suggested that this compound may be radioiodinated and used as a radioligand for further dopamine D3 receptor characterization.56 In addition, selected analogues were evaluated for intrinsic activity in the mitogenesis test in NG 108-15 cells expressing the hD3 receptor and measuring [3H]thymidine incorporation. All of these 2-methoxyphenylpiperazines showed a partial agonist profile in this test comparable to that of BP 897 (1) and further implied that this substitution pattern was responsible for this intrinsic activity and was in contrast to the 2,3-dichloro substitution that was reported by others to give a D3 receptor antagonist profile in all in vitro tests.54 A more recent report from the Stark group further elaborated on the (E)-3-(4-iodophenyl)acryl pharmacophore, replacing the 2-methoxyphenylpiperazine with an isosteric azabicyclic moiety to give a similar in vitro binding profile.57 Interestingly, this substitution rendered these analogues as full D3 receptor antagonists, as seen with the similarly substituted SB 277011 (2). Although SAR from several different labs appeared to be consistent with one another quite well, despite varying absolute affinity values likely due to differing assay conditions, one report appeared in which significant differences were described.58 A novel approach that implemented a hybrid design using the 2-aminotetralin base of the 7-OH DPAT with the alkyl-chain-linked phenylpiperazine of the now “classic” D3 receptor antagonists/partial agonists was investigated. Compound 9 displayed the highest D3 receptor affinity (Ki ) 1.75 nM) and selectivity over D2 receptors (122-fold) in the series and possessed a shorter linking chain (ethyl vs butyl), no amide functional group, and the unsubstituted phenylpiperazine.58 This is in sharp contrast to SAR developed in the arylbutylamide series of D3 receptor ligands27,50 and may represent a novel structural class of D3 ligands. Additional analogues and intrinsic activities of these novel compounds were disclosed recently.59 As a first approach to identifying novel parent ligands for modification, we chose a series of compounds from

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Figure 3. Representative D3 antagonists and partial agonists.

our synthetic library based on certain structural features that had been reported to be important for D3 receptor binding. These compounds were screened for displacement of [3H]YM-09151-2 in primate D2 and D3 and in human D4 receptors expressed in CHO cells. Unfortunately, none of these compounds demonstrated particularly interesting binding profiles. The few compounds that did display high-affinity binding at D3 receptors were not selective, and most of them showed low affinity at all three D2-family receptor subtypes.50 Another hybrid pharmacophore approach employing a 3D-structure molecular modeling and a structure-based database searching has recently been described.60 This study employed molecular modeling of the dopamine D3 receptor based on the crystal structure of the G-proteincoupled receptor (GPCR) rhodopsin. Structural refinement followed by docking experiments with R-(+)-7-OH DPAT provided a model of the active state of the D3 receptor based on both experimental and computationally derived data. In addition, a pharmacophore model based on the 3D structures of known D3-selective ligands was also developed, and this combined computational approach provided the basis for database searching for novel D3 receptor ligands. A relatively large “hit” list (>6000 compounds) was narrowed to a small subset (20) of compounds that were tested for D3 receptor binding.60 Although none of these “hits” demonstrated high-affinity binding to the dopamine D3 receptor, this approach may serve as the basis of other computationally derived methods to identify novel pharmacophores at the D3 receptor. Because of the fact that thus far the most potent and selective D3 antagonists/ partial agonists share a very similar structural base, additional novel approaches must be considered to optimize D3 receptor affinity and selectivity and to provide compounds that will be useful as in vivo tools. Because most of the potent and selective D3 compounds to date have very high lipophilicities (cLogD > 5), one approach has been to identify isosteric replacements of lipophilic moieties with functional groups that result in a less lipophilic and more bioavailable molecule. 3.1. Chemical Modification To Improve Bioavailability of D3 Receptor-Selective Molecules. The GlaxoSmithKline group who discovered SB 277011 (2) recently reported an excellent example of chemical modification to improve bioavailability of this D3 receptor-selective molecule. After the initial in vitro and in vivo characterization of SB 277011 (2),42 numerous reports further described its potential as an antipsy-

chotic or drug abuse medication in rodent models.61-63 These studies will be discussed further in section 6. Nevertheless, early in this drug development process, it was discovered that SB 277011 (2) was a substrate for aldehyde oxidase mediated metabolism and would likely have low bioavailability in humans.64 Thus, the search for a compound that would not be metabolized by this enzyme but would retain the excellent pharmacological profile of SB 277011 (2) was undertaken. Bioisosteric replacement of the tetrahydroisoquinoline moiety with a benz[d]azepine and substitution of the cyano group by a methanesulfonyl group resulted in a series of compounds that displayed both high affinity and selectivity for the D3 receptor. Analogue 10 was disclosed as having a particularly good pharmacological profile (hD3; pKi ) 8.4; Ki ) 4.0 nM) with 100-fold selectivity over D2 receptors and a panel of 60 other CNS receptors and ion channels.65 Further, compound 10 was a potent D3 antagonist with an excellent pharmacokinetic and CNS penetration profile in rat and was devoid of metabolism confounds that precluded further advancement of the parent compound SB 277011 (2) into human clinical trials.65 In our effort to improve the pharmacological profile and optimize bioavailability of NGB 2904 (4) by reducing lipophilicity, we also replaced the terminal fluorenyl group with heterocyclic ring systems51 (Figure 3). As reported by others,37,54-56 this modification was generally well-tolerated at the D3 receptor but did not improve the D3 selectivity profile of the resulting compounds compared to the parent compound NGB 2904 (4). For example, in this study, rat D3 and rat D2L receptors were expressed in Sf9 cells, and NGB 2904 (4) showed a remarkable 830-fold D3 selectivity when displacing the nonselective D2-like radioligand [125I]IABN. Whereas the heterocyclic analogues displayed comparable affinities at D3 receptors, they had much higher affinities than NGB 2904 (4) at D2 receptors under these conditions. As in the Hackling et al. study,56 p-iodophenyl replacement of the fluorenyl group resulted in a high-affinity D3 (Ki ) 1.4 nM) ligand with moderate selectivity (D2/D3 ) 63-fold). Incorporating structural rigidity into the butylamide linker by incorporation of alkynes was not tolerated at either D2 or D3 receptors. However, both the cis and trans olefins retained high affinities for D3 receptors while having moderate selectivities over D2 receptors.51 Intrinsic activities of selected compounds in this series were assessed using stimulation of mitogenesis or inhibition of

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Figure 4. SAR of D3 antagonists/partial agonists.

quinpirole-stimulated mitogenesis in CHO cells. However, unlike previous reports, some of these 2,3-dichlorophenylpiperazines demonstrated a partial agonist profile in this test. In this small set of seven compounds, no discernible SAR to predict efficacy could be deduced. The next generation of compounds was thus designed to incorporate both structural rigidity, via a trans olefin, and heterocyclic ring systems into these D3 ligands to optimize both D3 affinities and selectivities as well as to reduce lipophilicities to cLogD < 5 (Figure 3). We were encouraged by the published reports that suggested that heterocyclic substitutions such as the benzthiophene and benzofuran might yield highly selective and potent D3 antagonists54,55 because these compounds were members of our new series of D3 ligands in which we prepared both the saturated butylamides and their unsaturated trans olefinic analogues and systematically compared them in both binding and in vitro function.52 In this study we used hD2L, hD3, and hD4 receptors expressed in HEK 293 cells with the radioligand [125I]IABN and discovered that the D2/D3 selectivity ratios were significantly reduced over those obtained when testing in rat D2 and rat D3 receptors largely because of significantly higher affinities at hD2 receptors. For example, we reported that the parent compound NGB 2904 (4) had a binding affinity of 1.1 nM at rat D3 and 911 nM at rat D2 receptors, giving a D2/D3 ratio of 833,51 whereas in the human D2-like receptors, NGB 2904 (4) had a Ki ) 2 nM at D3 and Ki ) 112 nM at hD2L receptors, resulting in a significantly lower selectivity ratio of 56.52 Our initial study51 suggested that lipophilicity of these compounds could be reduced by replacing the bi- or tricyclic aryl terminus with a substituted phenyl ring and that the compounds could still maintain high binding affinity and selectivity for D3 receptors. An extended series of trans olefins tested in the human D2 receptors did not support this hypothesis. Although several compounds had high affinity for D3, none were >34-fold selective over D2 receptors. However, when the substituted phenyl rings were replaced with various heterocyclic aryl ring systems, subnanomolar binding affinities for D3 receptors were achieved and D3 selectivities were improved. The analogue PG01037 (24), having a 4-(2-pyridyl)phenyl terminus, was determined to be one of the most selective compounds in the series, showing a D2/D3 ratio of 133.

We then compared several heterocyclic analogues with either the saturated butyl or the unsaturated transbutenylamide linker to determine what role structural rigidity might play in the binding profile of these compounds. We discovered that in general the transbutylamide-linked heterocyclic analogues demonstrated binding affinities comparable to those of the saturated derivatives at D3 receptors (Ki ) 0.3-3.8 nM) but had lower binding affinities at D2 receptors, resulting in slightly better D3 selectivity profiles. All of these compounds had low binding affinities for D4 (Ki > 300 nM). In addition, all of the analogues tested antagonized quinpirole-stimulated mitogenesis in CHO cells in a D3selective manner.52 Furthermore, we discovered that in our hands, the saturated butylamide benzthiophene (6) and benzofuranyl (7) analogues were far less D3-selective than previously reported and that the unsaturated analogues of these compounds had a slightly better D2/D3 selectivity profile.52 The most interesting compound in this series (24) was significantly less lipophilic, as predicted by its cLogD ) 5.3, compared to the comparable benzthiophene analogue (23) with cLogD ) 7.1 or NGB 2904 (4) with cLogD ) 6.9. In total, this compound appears to be the most promising candidate in this series for in vivo testing and as such is currently being evaluated in several animal models of drug abuse. 4. SAR So Far The SAR for the most potent and selective D3 antagonists follow a very stringent skeleton. Thus, despite hundreds of compounds reported in the recent literature, few major modifications have been discovered to be tolerated at D3 and not tolerated at D2 receptors. This is likely due to the homology between D3 and D2L receptors, which exceeds 50% and is even higher in the transmembrane regions (78%), where these compounds are thought to bind.66 As such, optimal D2/D3 selectivity has thus far been achieved, as depicted in Figure 4, by the following: (1) an extended bi- or tricyclic aryl ring terminus that cannot be truncated to a single aryl ring unless extended from the amide moiety with a trans olefinic linker. This ring system can, however, be substituted with heteroatoms, resulting in retention or, in some cases, improvement in D3 binding affinities. If nitrogen is incorporated, lipophilicity will be reduced;

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however, to date, there appears to be a limit to how many nitrogens can be integrated into this terminus without detrimental results. (2) A butylamide linking chain is present in the majority of the most potent and selective D3 antagonists. However, substitution with a trans-butenyl or trans-cyclohexylethyl linker is also well-tolerated at D3 receptors and can improve the D3 selectivity profile. It is noted that alkyne substitution in this linking chain is not tolerated. (3) An azacyclic aryl ring terminus is required with the 2,3-dichlorosubstituted phenylpiperazine or the p-cyano or methanesulfonyl-substituted phenyl azacyclic ring systems as optimal. 2-Methoxyphenylpiperazine substitution tends to provide high D3 receptor affinities but reduces selectivities across other receptor systems. Intrinsic activity is difficult to predict on the basis of the SAR of these compounds. Although several labs have reported that the 2,3-dichloro-substituted analogues are always antagonists,54 in mitogenesis assays we have found otherwise.51 Likewise, the 2-methoxy-substituted phenylpiperazines have thus far been reported as D3 partial agonists,33,54 although in additional in vitro and in vivo models, this has been contested.27,40,41 The azabicyclic analogues of SB 277011 (2) have thus far consistently fallen into the D3 receptor antagonist category. 4.1. Inconsistencies between In Vitro Binding and Functional Affinity/Potency Values across Assays and Laboratories. In Table 1, the D2L, D3, and D4 receptor binding data are tabulated for the dopamine D3 ligands BP 897 (1), SB 277011 (2), NGB 2904 (4), and 17 structurally related analogues synthesized in our laboratory and by others. NGB 2904 (4) and its analogues have been tested under more than one binding assay condition across laboratories and thus are compared in this way. The presentation and discussion of binding data thus far in this perspective have been limited to those data published by the laboratory from which these compounds originally came. Because D3 SAR have been developed, overlap in the structures of some compounds has appeared, which has enabled direct comparisons of binding affinities across labs. This has led us to the observation that significant inconsistencies exist in the interpretation of “high affinity and selectivity” D3 receptor binding of these compounds. For example, as described previously, NGB 2904 (4) was first reported to bind to primate D3 receptors with Ki ) 1.4 nM and to primate D2 receptors with Ki ) 217 nM, giving a D2/D3 selectivity ratio of 155, which was the highest selectivity reported to date when this paper was published in 1998.48 When we tested NGB 2904 (4) in our assay, using rat D2L and rat D3 receptors in Sf9 cells and [125I]IABN as the displacement radioligand, the D3 receptor binding affinity did not change (Ki ) 1.1 nM) but the D2 receptor affinity was significantly lower (Ki ) 911 nM), resulting in a much more robust D2/D3 selectivity ratio of 830. We reasoned that because most of the animal models of drug abuse we use were conducted in rats, these in vitro data might be more relevant. Nevertheless, because a drug abuse medication will ultimately be used in humans, we have more recently gone to human D2L and D3 receptors in HEK 293 cells, using the same radioligand. In this case, NGB 2904 (4) still shows high affinity for D3 receptors (Ki ) 2.0 nM) but significantly higher affinity at hD2, result-

Perspective Table 1. Binding Data at D2-Receptor Subtypes for Selected D3 Ligands Ki ( SEM, nM compd

D2

1, BP 897 61 ( 0.2i 2, SB 277011 2820k 1050l 4, NGB 2904 217 ( 12a 911 ( 190c 112 ( 22f 698 ( 120g 5 89 ( 4b 19.4 ( 0.3g 70.1 ( 17h 6 3600 ( 950d 170 ( 10e 64.7 ( 8.9f 42.5 ( 18g 7 320 ( 10d 5740 ( 125e 44.8 ( 10.6f 119 ( 43g 10 398j 11 87.5 ( 33c 39.3 ( 10.0f 51.4 ( 1.4g 12 109.4 ( 5.3c 29.6 ( 9.0f 58.3 ( 19g 13 57.9 ( 5.1c 24.8 ( 8.6f 61.2 ( 18g 14 50.1 ( 6c 23.4 ( 6.4g 2.9 ( 1.0f 15 106 ( 22c >10000g 62.9 ( 13h 16 198 ( 39c 168 ( 29f >10000g 17 20.0 ( 1.8c 15.2 ( 3.7g 2.5 ( 0.9h 18 35.4 ( 7.6f 192 ( 14g 19 30.4 ( 3.8f 96.5 ( 17g 20 19.7 ( 3.6f 31.0 ( 0.1g 21 13.7 ( 4.8f 65.8 ( 17g 22 76.5 ( 14f 131 ( 29g 23 149 ( 7.9f 245 ( 61g 24 93.3 ( 12f 106 ( 22g

D3 0.92 ( 0.2i 10.7k 11.2l 1.4 ( 0.6a 1.1 ( 0.2c 2.0 ( 0.4f 2.7 ( 0.6g 1.4 ( 0.6b 4.9 ( 1.1g 4.0 ( 1.5h 0.5 ( 0.1d 0.14 ( 0.01e 0.8 ( 0.2f 2.6 ( 0.9g 1.5 ( 0.22d 0.62 ( 0.03e 0.8 ( 0.3f 4.3 ( 1g 3.98j 1.4 ( 0.5c 1.6 ( 0.5f 3.0 ( 0.7g 1.9 ( 0.7c 1.4 ( 0.1f 10.6 ( 0.0g 0.6 ( 0.2c 0.50 ( 0.2f 2.33 ( 0.8g 1.3 ( 0.4c 6.02 ( 1.3g 0.8 ( 0.1f 19 ( 7.8c 64.0 ( 6.4g 8.2 ( 2.3h 5.9 ( 1.8c 1.5 ( 0.1f 5.0 ( 1.1g 4.9 ( 1.9c 2.64 ( 0.7g 0.4 ( 0.0h 3.4 ( 0.6f 6.6 ( 0.2g 1.2 ( 0.2f 12.0 ( 4.4g 0.7 ( 0.1f 3.5 ( 0.1g 0.4 ( 0.0f 1.72 ( 0.4g 2.1 ( 0.5f 7.11 ( 0.0g 1.1 ( 0.0f 3.30 ( 0.4g 0.7 ( 0.1f 2.11 ( 0.1g

D4 300i >5000a

1850 ( 106b 1116 ( 236h 340 ( 10d >800 (38%)e 93 ( 18d 890 ( 125e

363 ( 111h 1020 ( 160f

1070 ( 380f 1770 ( 390f 375 ( 18f

D2/D3 66 263 93 155 830 56 259 64 4 18 7200 1214 81 16 213 9300 56 26 100 63 25 17 58 21 6 97 50 27 39 4 4 6 >156 8 34 112 >2000 4 6 6 10 29 25 8 28 9 34 38 36 18 135 74 133 50

a Reference 48, primate D2L, primate D3, hD4 in CHO cells; [3H]YM-09151-2. b Reference 50, primate D2L, primate D3, hD4 in CHO cells; [3H]YM-09151-2. c Reference 51, rat D2L, rat D3 in HEK 293 cells; [125I]IABN. d Reference 54, hD2L, hD3, hD4 in CHO cells; [3H]spiperone. e Reference 55, hD2L, rat D3, hD4 in Sf9 cells; [3H]spiperone. f Reference 52, hD2L, hD3, and hD4 in HEK 293 cells; [125I]IABN. g CTDP unpublished data, hD2L, hD3, hD4 in CHO cells; [3H]YM-09151-2. h Luedtke unpublished data, hD2L, hD3, and hD4 in HEK 293 cells; [125I]IABN. i Reference 33, hD2, hD3, hD4 in CHO cells; [125I]iodosulpride (D2 and D3), [3H]spiperone (D4). j Reference 65, calculated from reported pKi values (hD2L, hD3 in CHO cells; [125I]iodosulpride). k Reference 61, calculated from reported pKi values (rat D2, rat D3 in CHO cells; [125I]iodosulpride). l Reference 61, calculated from reported pKi values (hD2L, hD3 in CHO cells; [125I]iodosulpride).

ing in a far less robust D2/D3 selectivity ratio of 56. NGB 2904 (4) has also been evaluated in NIDA’s Cocaine Treatment Discovery Program (CTDP) that also

Perspective

employs cloned hD2L and hD3 receptors, however, in CHO cell lines and [3H]YM-09151-2 as the displaced radioligand. Largely because of a comparatively lower affinity at D2 receptors (Ki ) 698 nM), NGB 2904 (4) was found to be 259-fold D3-selective over D2 receptors under these assay conditions (Table 1). In our first report of NGB 2904 (4) analogues, we highlighted compound 5 as having the highest D3 affinity (Ki ) 1.4 nM) and selectivity (D2/D3 ) 64) in our series of novel compounds.50 These binding data were obtained in primate D2 and D3 receptors. When we tested this compound, using human D2 and D3 receptors in HEK 293 cells, the ratio fell to D2/D3 ) 18. Surprisingly, CTDP found a D2/D3 ratio of 4. Had we initially relied on these latter data, we would likely not have followed that compound as a lead for further investigation. This trend was also observed with several of our second-generation heterocyclic butylamide analogues (11-13) that were first tested in rat D3 and D2L receptors and later in human receptors either in the Luedtke laboratory or by CTDP. In fact, the initial characterization of the cis vs trans butenyl linker led us to believe that the trans olefins were significantly more selective than the cis (14 vs 17).6 However, we discovered later that at the hD2L and hD3 receptors, this difference in selectivity was not as robust. Nevertheless, we had already embarked on a synthetic program synthesizing trans olefins, and this followed the SAR of the SB 277011 (2) series of compounds. However, in the trans olefin series, another trend became apparent wherein compounds such as 16 (which showed a moderate D2/D3 ratio ) 34 at the rat D2-like receptors) when tested at human receptors, primarily because of high affinity at hD3, had a D2/D3 ) 112, making it one of the most selective compounds in our series. Interestingly, the CTDP data, also derived from human D2-like receptors, but using different cell lines and radioligands, showed two of the compounds in this series, 15 and 16, to be inactive at hD2L receptors at 10 µM and thus were deemed highly selective D3 receptor ligands. When the selectivity ratios were compared for the rest of the compounds in Table 1, there was not an absolute trend nor consistently high D3 receptor binding in one assay resulting in higher (D2/ D3) selectivity ratios, for example. We believe that describing selectivity ratios across species is particularly risky because there does seem to be significant differences, especially in the absolute Ki values at D2L receptors for rat vs humans. Nevertheless, human D2like receptors expressed in different cell lines and/or using different radioligands yield significantly different Ki values, which result in very different D2/D3 selectivity ratios. One of the most robust examples of this is with compounds 6 and 7, which were reported previously by both the Gmeiner and the Leopoldo groups as displaying extraordinary D3 selectivity (Table 1). Nevertheless, when we synthesized and tested these compounds in our laboratory, only moderate D2/D3 selectivities were observed (D2/D3 ) 81 and 56, respectively). Likewise, CTDP data showed even lower selectivities, with significantly lower affinities at D3 and significantly higher affinities at D2L than were originally reported. With the exception of the D3 data in the Leopoldo et al. paper, which were obtained in cloned rat rD3 receptors,

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3671 Table 2. In Vitro Functional Data at D2-Receptor Subtypes for Selected D3 Ligands IC50, nM compd

hD2

hD3

1280 ( 270b,e 35.6 ( 12.6 (44)b,d 94.7 ( 18b,e 118 ( 14b,e 55.4 ( 20b 76.7 ( 12b 92.0 ( 4.9 (22)b,d 16.1 ( 4.3b ND IAb,h 7.49 ( 0.1b 162 ( 51b,e 61.8 ( 21b,e 13.8 ( 1.0b,e 8.29 ( 2.1b,e 111 ( 18b,e 254 ( 35b,e 80.9 ( 6.7b,e

3 ( 1 (55)d,f 1.8 (56)g 5.0a 14.4 ( 0.5b,e 14.6 ( 0.6 (57)b,d 4.94 ( 0.31b,e 9.01 ( 1.4b,e 31.7 ( 10 (30)b-d 26.8 ( 7.7b,c 6.31 ( 1.7 (30)b-d 7.71 ( 1.6b,c 114 ( 32b 173 ( 9.6 (44)b-d 6.00 ( 0.59b,c 24.1 ( 3.4b,e 4.79 ( 1.8b,e 2.2 ( 0.5b,e 1.00 ( 0.09b,e 18.7 ( 2.8b,e 9.62 ( 0.6b,e 3.01 ( 0.7b,e

1, BP 897 4, NGB 2904 5 6 7 11 12 13 14 15 16 17 18 19 20 21 22 23 24

D2/D3

89 2 19 13 2 3 15 2 >100 1 7 13 6 8 6 26 27

a Reference 48, hD3 in CHO cells; antagonized 100 nM quinpirole-stimulated mitogenesis. b CTDP, hD2, or hD3 in CHO cells; stimulated mitogenesis or antagonized 30 nM quinpirole-stimulated mitogenesis. c Reference 51. d Partial agonist (% stimulation). e Reference 52. f Reference 33, hD3 in NG 108-15 cells; stimulated mitogenesis. g Reference 54, hD3, hD4 in CHO cells; stimulated mitogenesis. h IA: inactive.

all of these Ki values were derived from hD2-like receptors. However, the absolute values were vastly different, which provides a significant challenge to medicinal chemists trying to identify pharmacophores and functional groups that will optimize both pharmacological specificity and bioavailability. 5. In Vitro Functional Data as a Measure of Intrinsic Activity and D2/D3 Selectivity It might be argued that binding data in cloned receptors expressed in cell lines and tested under nonphysiological conditions should only be used as an initial guide to receptor activity and that in vitro functional assays are more predictive of in vivo action and receptor selectivity. Although different laboratories use different in vitro tests, the mitogenesis assay for intrinsic activity at D2-like receptors appears to be one common model, even if only D3 efficacy is routinely reported and thus D2/D3 selectivity can rarely be ascertained. In Table 2, BP 897 (1), NGB 2904 (4), and a series of compounds synthesized in our laboratory are compared using this in vitro functional test to assess both intrinsic activity and D2/D3 selectivity. NGB 2904 (4) was first described as a D3-selective antagonist with an EC50 ) 5.0 nM in the mitogenesis assay using hD3 receptors in CHO cells.48 CTDP also evaluated this compound and provided data to support a D3-selective antagonist profile, but the compound was ∼3-fold less potent than from the original report. Compounds 5 and 11 were also evaluated by CTDP, and we reported these compounds as D3 partial agonists but with a D2/D3 selectivity ratio of 2. It should be noted that compound 5 is very closely related to NGB 2904 (4) in structure with the only difference being a 4-fluorenone substituent compared to the 2-fluorene in NGB 2904 (4). The partial agonism displayed by 5 and additional data supporting NGB 2904 (4) as a full antag-

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Perspective

onist are puzzling. Likewise, 12 is a very close derivative of the heterocyclic analogue 13, and yet it was found to be moderately potent but essentially a nonselective D3 antagonist and that 13 was a more potent (∼4-fold) D3 partial agonist with a D2/D3 ratio of 15. In this assay, 6 and 7, which were originally reported to be extraordinarily potent and selective D3 antagonists, showed moderate selectivity (19- and 13-fold, respectively) but were >600-fold less potent in the functional assay than the Ki values in the binding assay predicted. Compound 16 likewise was much less potent in the functional assay (EC50 ) 173 nM vs Ki ) 5 nM) but like the binding assay was without activity at 10 µM, further supporting high D3 selectivity. This compound was the only butenylamide of the series that showed a partial agonist intrinsic activity. All of the other olefins were antagonists at both D3 and D2L receptors under these assay conditions. Moreover, 23 and 24 were the most D3 selective analogues, with the latter being 5-fold more potent than the parent compound NGB 2904 (4), at the D3 receptor but not as selective (D2/D3 ) 30). Because the comprehensive data set on D2 and D3 receptor intrinsic activity in this or any other in vitro assay has not been reported for a large and structurally diverse series of D3 compounds, it is impossible to predict which structural features will provide intrinsic activity and which will not. Also, it is certainly possible that in another in vitro functional assay, such as the microphysiometry measure of agonist-induced extracellular acidification rates, all of these compounds would be antagonists. At this stage, it is premature to speculate on SAR for in vitro function at the D2-like receptors, based on the published literature. Further in vitro and in vivo evaluation of a series of purported D3-selective antagonists and partial agonists must be performed and compared in order to reliably predict efficacy in vivo. Although these data may be available in individual pharmaceutical companies, they remain out of the public domain.

novel and selective dopamine D3 receptor ligands.73,74 Studies were subsequently published showing that the moderately (10-fold) D3 selective antagonist nafadotride75 blocked the development of locomotor sensitization to amphetamine in rats.76 However, because of nafadotride’s modest selectivity and unknown D3 receptor occupancy, D3 blockade as the only explanation for these effects remain to be determined. Prior to describing specific D3 receptor compounds, a brief discussion of some of the in vivo animal models related to drug abuse will be highlighted. These can be considered along two broad dimensions: unconditioned behaviors and conditioned behaviors. For this review, locomotor activity is the unconditioned behavior described. With regard to conditioned behaviors and drug abuse, three models are frequently employed: conditioned place preference (CPP), drug discrimination, and drug self-administration. In studies using CPP, the drug of abuse (e.g., cocaine) is paired with a distinct environment while vehicle injections are associated with a different environment. Dopamine D3-selective compounds can be examined for their ability to induce CPP or to block cocaine-induced CPP. In drug discrimination, animals are trained to make a response when they receive a drug (e.g., cocaine) and make a different response when they receive vehicle. Again, dopamine D3-selective compounds can be studied for their ability to share cocaine-like discriminative stimulus effects and for their ability to shift the cocaine dose-response curve. The third model is drug self-administration, in which animals are trained to press a lever for intravenous injections of drugs. The schedule of drug availability can have a profound effect on the ability of D3 compounds to block or potentiate the reinforcing effects of drugs of abuse (as discussed below). 6.1. Cocaine. Modulation of cocaine self-administration by the purported D3 receptor selective agonist (+)7-OH DPAT was first reported in 1993.77 Despite the lack of pharmacologic specificity of (+)-7-OH DPAT, this study provided a seminal initiation to associating dopamine D3 receptors with cocaine abuse and, further, provided data that supported a focus on the dopamine D3 receptor as a potential therapeutic target for medication development. Another report using (+)-7-OH DPAT, its racemate, and the nonselective D2/D3 agonist, quinpirole, showed all three agonists fully substituted for cocaine in rhesus monkeys trained to discriminate cocaine from saline.78 These studies pointed to the need for highly selective D3 agonists and antagonists for in vivo study. While medicinal chemists were toiling toward synthesizing potent and selective D3 ligands, several additional discoveries supported this endeavor. For example, quantitative in vitro autoradiography using [3H]-(+)-7-OH-DPAT as the radioligand showed a significant elevation of dopamine D3 receptor density in cocaine overdose victims compared to drug-free and age-matched controls.79 In addition, an up-regulation of D3 receptor mRNA was also observed in human cocaine overdose victims, further supporting the hypothesis that chronic cocaine exposure results in adaptive changes in dopamine D3 receptors,80 although actual up-regulation of protein synthesis was not demonstrated. In animal studies, D3 receptor antisense administration intracerebroventricularly by osmotic minipump, to

6. D3 Receptors and Drug Abuse Abused substances such as cocaine, heroin, ethanol, and nicotine interact at various neural foci in the brain reward circuitry to elicit pharmacological actions that are deemed pleasurable and may lead to addiction. The common neurotransmitter, dopamine, is elevated in the nucleus accumbens originating from the ventral tegmental region, and thus, dopamine receptor subtypes have been the target for potential pharmacotherapeutic strategies.67-69 The dopamine D3 receptor has been the focus of significant interest because of its discrete neuroanatomical location, particularly the nucleus accumbens shell,69 and its higher affinity for dopamine compared to other dopamine receptor subtypes.70 The D3 receptor gene became a candidate for further study in mental disorders.66 Several excellent reviews have described the neurobiology and clinical potential of targeting the dopamine D3 receptor.19,71,72 The goal of discovering novel antipsychotic agents that were devoid of debilitating side effects provided the catalyst for many pharmaceutical companies to pursue the design and synthesis of novel dopamine D3 receptor ligands. Furthermore, the deduction that dopaminergic pathways involving psychosis were also involved in drug reinforcement and behavioral sensitization provided further incentive to pursue the discovery and development of

Perspective


reduce (28%) the number of central dopamine D3 receptors, resulted in increases in spontaneous locomotor activity of nonhabituated rats.81 Consistent with findings described above, Neisewander et al.82 recently reported that rats allowed to self-administer cocaine and then made abstinent for 1 month showed increases in D3 receptor densities in the nucleus accumbens core and ventral caudate-putamen, suggesting a regulatory response of D3 receptors to cocaine exposure. The initial report on dopamine D3 receptor mutant mice, however, found identical behavioral effects of D3 agonist PD 128907 and D3 antagonist nafadotride compared to wild-type mice.24 These investigators concluded that on the basis of these studies in genetically mutated mice, it was unlikely that D3 receptors were involved in either thermoregulation or modulation of locomotor activity under normal conditions.24 Recently, another study investigating the locomotor activity effects of D2/D3 agonists and antagonists, with varying selectivities, concluded that the most selective D3 antagonists studied did not show significant effects on locomotor behavior in rats.83 Further, selective blockade of D2 but not D3 receptors alone suppressed motor function, and yet the authors noted that mechanisms underlying behavioral differences observed for structurally diverse D3 receptor antagonists remained to be elucidated.83 In another study of the role of D2-like dopamine receptors on locomotor stimulant effects in mice, Chausmer and Katz84 concluded that D2-like antagonists suppressed locomotor activity alone and attenuated cocaine-induced locomotor activity, further supporting a role of this D2family of receptors in the locomotor activity produced by cocaine. Nevertheless, species differences between mice and rats and their response to D2-like receptor agonists and antagonists have been noted. It is also important to point out that while there appears to be a relationship between locomotor activity and vulnerability to drug abuse,85 others have questioned this baseline as a model of drug abuse.86 In another report, dopamine D2 receptor deficient (homozygous and heterozygous) mice were trained to self-administer cocaine and then the effects of the nonselective D2 receptor antagonist eticlopride and the agonist quinelorane were assessed.26 This study showed that eticlopride did not modify cocaine self-administration in the D2 knockout mice, despite having fully intact D3 and D4 receptor subtypes. This suggested that the D2 receptor is not required for cocaine reinforcement and that blockade of D3 and/or D4 receptors by the D2like antagonists had no effect on self-administration.26 However, developmental factors and physiological and baseline behavioral activity of genetically modified mice might produce confounds in the comparison of these animals to wild-type mice and rats. A more D2-selective antagonist L741,626 dose-dependently and significantly increased cocaine self-administration in rats, whereas the D3/D4-selective antagonist L-745,829 and the D4selective antagonist L-745,870 had no effect.26 In combination, these studies seemed to refute a significant role for D3 in cocaine self-administration in rats and D2 mutant mice. This appears to contrast to both human and primate studies showing that lowered levels of dopamine D2-like receptors are predictive of cocaine’s pleasurable effects and self-administration rates, re-

spectively.87,88 Also, it appears that D2 and D3 receptors can be regulated in opposing fashions by chronic drug administration.79,89 Caine and colleagues argue that D2 receptor levels may reflect neuroadaptations to chronic cocaine use that contributes to cocaine addiction.26 Consistent with this finding was the observation that the reinforcing effects of 7-OH-DPAT were evident in monkeys with an extensive cocaine history but not in cocaine-naive monkeys.90 A selective D3 antagonist, or indeed a highly D2-selective antagonist whose temporal brain occupancies of D2 or D3 receptors can be quantitated, may be required to rule out pharmacokinetic and/or confounding pharmacological contributions to the lack of effect of these drugs on cocaine self-administration. As described above, the first dopamine D3 receptor selective partial agonist, BP 897 (1), was discovered to reduce cocaine-seeking behavior maintained by a cocaineassociated cue, without decreasing cocaine self-administration.33 Because BP 897 (1) was not self-administered, these data suggested that it reduced motivational effects of cocaine-related cues and thus reduced drug seeking in these animal models without the potential confound of having cocaine-like effects.69 Additional studies confirmed that BP 897 (1) was not a positive reinforcer in monkeys and did not generalize to either the cocaine or methamphetamine discriminative stimulus.39 Moreover, BP 897 (1) dose-dependently attenuated the cocaine and methamphetamine stimulus effects, further supporting its potential as a cocaine-abuse therapeutic agent.39 The logic behind the development of a partial agonist comes from significant evidence supporting the abuse liability of nonselective agonists and the thus far unsuccessful discovery of highly dopamine receptor subtype-selective agonists. Antagonists have demonstrated their ability to block cocainelike actions, and this has provided the speculation of why animals will increase their rates of cocaine selfadministration in the presence of a nonselective D2 antagonist. Also, extrapyramidal side effects associated with the D2-like antagonists would likely reduce compliance and successful cocaine abstinence.18 Thus, an agonist with low intrinsic activity would maintain a low level of dopamine receptor activation and as such might prevent cocaine-seeking behavior while serving as an antagonist to high levels of synaptic dopamine due to relapse to cocaine taking. Thus, support for targeting dopamine D3 receptor agonists with low intrinsic activity to affect the acute reinforcing effects of cocaine and to potentially thwart relapse has been promoted.91 Nevertheless, sufficient data to support the development of dopamine D3 partial agonists over D3 antagonists have not appeared. In fact, SB 277011 (2), a selective D3 antagonist that has a similar if not more selective pharmacological profile than BP 897 (1), has also demonstrated substantial promise in preclinical models of cocaine abuse. The first reports using the D3-selective antagonist SB 277011 (2) to determine the acute effects of dopamine D3 receptor antagonism in various rodent models of cocaine reinforcement appeared recently.62,63 One study demonstrated that SB 277011 (2, 3.0 mg/kg, ip) blocked the cocaine-induced enhancement of brain stimulation reward while having no effect on brain stimulation

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Table 3. Locomotor Activity in Swiss-Webster Mice for Selected D3 Ligands1 compd 4, NGB 2904 11 13c 15 16 23 24c

LMA ID50 (mg/kg) 138b 85.1 31.6 144.5b IAe 572b 52.4

n, male Swiss-Webster mice

cLogD d

8 8 8 8 8 8 8

6.94 6.20 5.30 7.07 7.07 7.10 5.34

a A dose-response study was conducted using a standard protocol under NIDA Contract N01DA-7-8822. Doses of 3, 10, 30, or 100 mg/kg test compound were dissolved in 2% methylcellulose and injected ip with a 20 min pretreatment time. Interruption of photocell beams was measured for 1 h and recorded in 10 min time periods. b Extrapolated over a 0-30 min time period. c H2Osoluble; IA, inactive up to 100 mg/kg. d Calculated partition coefficients at physiological pH 7.4. ACD/LogD Suite; Advanced Chemistry Development Inc.: Toronto, Canada. e IA: inactive.

reward thresholds by itself at this or higher doses. Likewise, SB 277011 (2) blocked both the acquisition and expression of cocaine-induced conditioned place preference, suggesting that D3 receptor blockade specifically was involved in the behavior of cocaine-taking.62 Although a subsequent report did not verify this finding with SB 277011 (2) or the other dopamine D3-selective agonists and antagonists 7-OH DPAT, PD 128907, nafadotride, or BP 897 (1),92 CPP remains a controversial model of reward and certainly alone cannot predict medication potential for drug abuse. In another model of cocaine-triggered relapse wherein cocaine reinstatement is induced after an extinction period, SB 277011 (2) produced a dose-dependent attenuation of cocaine-induced relapse.62 These data supported the further development of SB 277011 (2) as a potential medication for cocaine abuse and further verified a modulatory role for D3 receptors in cocainetaking behavior.62 In another set of experiments, with a second-order schedule of reinforcement that provides another model of cocaine seeking, SB 277011 (2) dosedependently decreased cocaine seeking while having no effect on cocaine intake in another model that uses a fixed ratio 1 (FR1) schedule of reinforcement.63 The latter finding was supported by an additional report92 and is in contrast to previously described studies on nonselective antagonists that appear to block the rewarding effects of cocaine and hence cause an increase in cocaine self-administration. Experiments similar to those described for SB 277011 (2), using the D3 antagonist NGB 2904 (4), have been communicated in a preliminary set of findings.93 As with SB 277011 (2), NGB 2904 (4) was observed to dosedependently attenuate cocaine self-administration (iv) under conditions that measure the animal’s motivation to self-administer cocaine (termed progressive-ratio schedule).93 Furthermore, NGB 2904 (4) also attenuated cocaine-induced reinstatement; these behaviors were prolonged (2-3 days) after a single dose of NGB 2904 (4) was administered. NGB 2904 (4) alone had no effects on locomotor activity in rats,93 although a suppression of locomotor activity in mice has been observed at higher doses in a different lab (Table 3). These preliminary data further support the independent findings that the dopamine D3 receptor is involved in both cocaineseeking and other cocaine-induced behaviors and that,

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in the cases of SB 277011 (2) and NGB 2904 (4), these behaviors may be modified through dopamine D3 receptor antagonism. Because only the acute effects of either of these drugs or the D3 partial agonist BP 897 (1) have been characterized, chronic effects as well as further understanding the role of intrinsic activity in vivo remain a goal in the development of these agents as potential cocaine abuse medications. Several of our novel agents are currently being evaluated in these and other models of cocaine abuse. The effects of 11, 13, 15, 16, 23, and 24 on spontaneous locomotor activity in Swiss-Webster mice are presented in Table 3 and compared to NGB 2904 (4). In this preliminary study, doses of 3, 10, 30, or 100 mg/kg were administered ip 20 min prior to the mice being placed in a standard locomotor activity chamber, where interruption of photocell beams were measured for 1 h. The ID50 values were recorded over the 0-30 min time period and in some cases extrapolated. NGB 2904 (4) at the lowest dose produced a trend toward increasing locomotor activity at the later time points (data not shown). However, at the higher doses, spontaneous locomotor activity was suppressed compared to vehicle, with an extrapolated ID50 value of 138 mg/kg. Interestingly, compound 24 showed this trend at the lowest dose tested and at the early time points (data not shown) but, like NGB 2904 (4), showed overall suppression of a locomotor activity with an ID50 ) 52.4 mg/kg. Likewise, all but compound 16 showed suppression of locomotor activity, with compound 13 exhibiting the highest potency (ID50 ) 31.6 mg/kg). Both 13 and 24 bind with high affinity to the dopamine D3 receptors and are distinguished from the other members of this group of compounds as having the lowest lipophilicities, as measured by cLogD values, and being H2O-soluble. Nevertheless, with this small subset of compounds, it is impossible to draw mechanistic/bioavailability conclusions regarding D3 receptor association with suppression of locomotor activity in mice. Indeed, at the doses evaluated, blockade of both D2 autoreceptors and postsynaptic D2 receptors are likely contributors to these actions on motor behavior in mice. As discussed previously, the D2 receptor family is undoubtedly involved in motor function and further may play an important role in cocaine-induced locomotion.83,84 However, the role of the D3 receptor subtype in locomotor activity and other cocaine-related behaviors remains an area for further investigation. 6.2. Heroin. A short communication suggesting that the findings with SB 277011 (2) in models of cocaine abuse might also be replicated in similar models of other illicit drugs of abuse, such as heroin, has appeared recently.94 These studies may provide a broader basis for dopamine D3 receptor modulation of drug seeking behavior, associated with mechanisms of action more indirectly related to dopamine receptors. Heroin is the 3,6-diacetylated analogue of the prototypical µ-opioid receptor agonist morphine and a powerful drug of abuse. Although heroin and its deacetylated metabolite(s) bind directly to central opioid receptors as their primary mechanism of action, subsequent and indirect stimulation of dopamine receptors in the limbic regions of the brain is involved in their rewarding effects.95,96 However, the specific role of the dopamine D3 receptors in

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heroin-induced reward is unknown, and thus, complementary studies on the effects of acquisition and expression of heroin-induced conditioned place preference using SB 277011 (2) were performed. As in the cocaine study, SB 277011 (2, 10 mg/kg) did not show conditioned place preference or aversion alone but blocked both the acquisition and expression of heroin-induced CPP.94 While these studies provide some data to support a potential D3-mediated mechanism in these behaviors, further investigation is required in order to determine whether a D3 antagonist, such as SB 277011 (2), would indeed provide a nonopioidergic approach to heroin abuse medication. 6.3. Nicotine. Tobacco smoking produces the greatest cost to society in terms of medical consequences, compared to all other abused substances.10,97 Although nicotine replacement therapy and bupropion (Zyban) are prescribed for smoking cessation, relapse remains high and is often elicited by environmental cues. In animals, drug-associated environmental stimuli can produce reinforcing effects and maintain responses after drug extinction,98 and this model was used to show the effectiveness of BP 897 (1) on cocaine-seeking behavior.33 The concept that reducing the effects of nicotineassociated cues, presumably elicited through a common limbic dopaminergic mechanism, might ultimately prevent relapse to nicotine-seeking suggested that BP 897 (1) or other dopamine D3-selective agents might also show promise in this model. Indeed, nicotine cueconditioned hyperactivity in rats caused dopamine D3 receptor overexpression, as measured by in vitro autoradiography using [3H]-(+)-7-OH DPAT as the displacement radioligand.99 Moreover, both BP 897 (1) and SB 277011 (2) inhibited locomotor hyperactivity elicited by the nicotine-paired environment but were ineffective in attenuating the nicotine-induced conditioned locomotor activity.99 These results suggest that as a mechanistic target for incentive motivational actions, the D3 receptor may provide a target for more general therapeutic application than just cocaine abuse. By disrupting conditioning to environmental stimuli, these D3 partial agonists and antagonist may have therapeutic potential in smoking cessation.99 In a parallel study, SB 277011 (2) was also discovered to significantly antagonize nicotine-induced reinstatement without affecting nicotine self-administration.100 Whereas in previous studies the nonselective D2 antagonist haloperidol dose-dependently produced “extinction-like intrasession reduction“ of nicotine self-administration,101 it has been reported to increase smoking in schizophrenic and nonpsychiatric patients.102-104 Thus, the data showing that the selective dopamine D3 antagonist SB 277011 (2) had no effect on nicotine taking but instead attenuated nicotineinduced reinstatement provide additional preclinical support to the therapeutic potential of D3 antagonists or partial agonists for smoking cessation. 6.4. Ethanol. The mechanistic basis for alcohol abuse remains ill-defined. However, involvement of the mesolimbic dopaminergic system, and particularly dopamine D3 receptors, in ethanol reward has been described.105 Early studies with nonselective or only moderately selective D3 ligands such as 7-OH DPAT or U-99194A suggested a potential role for D3 receptors in modulating alcohol intake.106,107 Moreover, studies in

D3 knockout mice showed modest differences in withdrawal symptoms as a result of terminating chronic ethanol exposure.108 However, interpretation of these results are complicated by the lack of selectivity of the pharmacological tools and the genetically mutated mice that undoubtedly have developmental and compensatory modifications in their dopaminergic systems as a result of the D3 receptor deletion. Preliminary reports on the effects of the selective D3 antagonist SB 277011 (2) showed that high doses (10-30 mg/kg, ip) as opposed to low doses (100 while maintaining lipophilicities that are within a “drug-like” range (e.g., cLogD < 5) continues to be a challenge and has further limited the pharmacological utility of the currently available agents. Moreover, because in vitro binding and functional data are obtained in different laboratories using different assay conditions, inconsistencies prevent across-lab comparisons and thus provide another obstacle to novel drug design. These challenges have also contributed to the lack of selective radioligands for in vitro assays in brain tissue rather than using cloned receptors transfected into various cell lines. Furthermore, the current lack of selective D3 receptor PET ligands for in vivo brain occupancy studies is problematic. Several recent reports have suggested potential PET ligands;56,109,110 however, success in brain imaging with these ligands has yet to be established and appears unlikely because of lack of receptor selectivity and unfavorable lipophilicities. Alternative approaches that can allow visualization of D3 receptors using the nonselective D2/D3 ligand [11C]raclopride are underway.111 However, having a selective D3 receptor PET ligand would provide the ideal

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tool for elucidating brain occupancy, in real time, and to further assess effects of substance abuse, as well as potential D3-based medications on dopamine D3 receptors in vivo. Another challenge that requires significant study is establishing in vitro functional assays that actually predict in vivo function at dopamine D3 receptors. The intrinsic activity debate over whether partial agonists or antagonists hold the most promise for development as medications to treat drug abuse will remain until in vivo efficacy is established. At this time, in vitro functional assays are not necessarily consistent; i.e., BP 897 (1) shows both partial agonist and antagonist profiles, depending on which assay is used to measure intrinsic activity. Furthermore, SAR to predict efficacy are lacking in part because of the limited evaluation of ligands in multiple in vitro functional assays. Because the tools that have already been developed continue to help answer these questions and novel ligands are also discovered, acute studies will have to be supplemented with chronic studies in vivo because the roles of both pre- and postsynaptic dopamine D3 receptors will undoubtedly be modified as a result of chronic interaction with these drugs. How, for example, chronic blockade of these receptor populations will affect behavior and whether the acute effects of these agents on drug abuse are relevant to chronic effects are all topics for future investigation. Preclinical generalizability across substances of abuse will need to be further established using a combination of existing pharmacological and genetic tools and animal models of drug abuse. Furthermore, selectivity for these substances over “natural” rewards such as food should also be investigated.112 Each new discovery and the development of novel tools across disciplines will ultimately establish the role of dopamine D3 receptors in drug abuse and illuminate the future for development of D3 antagonists and partial agonists as drug abuse medications.

Peter Grundt received his doctorate in Organic Chemistry from Universita¨t GH Duisburg, Duisburg, Germany, in 1998. After postdoctoral work at the Universities of Bristol and Bath in the U.K., he became a Foreign Visiting Fellow within the Intramural Research Program of the National Institute on Drug Abuse (NIDA-IRP). Michael A. Nader received his doctorate in Experimental Psychology from the University of Minnesota, Minneapolis, MN, in 1985. After his postdoctoral work at Uniformed Services University of the Health Sciences in Bethesda, MD, he went to the University of Chicago where he was a member of the Research Faculty. He has been at Wake Forest University School of Medicine since 1992, where he is a Professor of Physiology/Pharmacology and Radiology and the Director of the Graduate Program. He has over 70 journal articles describing preclinical models of drug abuse.

Acknowledgment. We acknowledge Dr. Michael Robarge, J. J. Cao, C. J. Bennett, and E. Carlson for synthetic contributions to this project. We acknowledge Dr. Robert Luedtke for obtaining binding data and Dr. Rik Kline, Division of Treatment Research and Development, NIDA, for obtaining the CTDP data (Contract N01DA-1-8816). We thank Drs. Jon Katz, S. B. Caine, C. Ashby, and Z.-D. Xi for the helpful discussions during the preparation of this manuscript. This work was funded by the NIDA-IRP and Grants DA12460 (M.A.N.) and DA14637 (M.A.N.). Biographies Amy Hauck Newman received her doctorate in Medicinal Chemistry from the Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, in 1985. After postdoctoral studies at the National Institute on Diabetes, Digestive and Kidney Diseases, National Institutes of Health (NIH), she joined the Intramural Research Program of the National Institute on Drug Abuse (NIDA-IRP), NIH. She is currently a Senior Investigator and Chief of the Medicinal Chemistry Section, Medications Discovery Research Branch. She has coauthored more than 110 original articles and reviews on the design, synthesis, and pharmacological evaluation of CNS active agents, with an emphasis on the development of selective ligands for the dopaminergic system, as leads toward potential treatment medications for cocaine abuse.

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