Return of D4 Dopamine Receptor Antagonists in Drug Discovery

Perspective pubs.acs.org/jmc

Return of D4 Dopamine Receptor Antagonists in Drug Discovery Miniperspective Craig W. Lindsley*,†,§,‡,∥ and Corey R. Hopkins*,⊥ †

Department of Pharmacology, and ‡Vanderbilt Center for Neuroscience Drug DiscoveryVanderbilt University School of Medicine, Nashville, Tennessee 37232, United States § Department of Chemistry, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States ⊥ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States ABSTRACT: The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D4 antagonists that were developed for schizophrenia failed in the clinic. Thus, D4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D4 ligands with improved selectivity for D4 against not only D1−3,5 but also other biogenic amine targets have emerged, and D4 is once again in the spotlight as a novel target for both addiction and Parkinson’s disease (PD), as well as other emerging diseases. This report will review the historical data for D4, review the known D4 ligands, and then highlight new data supporting a role for D4 inhibition in addiction, PD, and cancer.

1. INTRODUCTION 1.1. Dopamine Receptors. As there are over 50 years of excellent reviews on different aspects of dopamine receptors,1−4 we will provide a brief overview to set the stage for the readers unfamiliar with the topic. Dopamine (1), a catecholamine neurotransmitter, is a predominant neurotransmitter in the mammalian CNS and periphery with a myriad of physiological functions including movement, emotion, cognition, food intake, reinforcement/reward, cardiovascular function, hormone secretion, and renal function to list but a few.1−4 After dopamine was recognized as a neurotransmitter in the 1950s,5 Cools and van Rossum rationalized that there must be multiple dopamine receptors (DRs) to facilitate the broad actions of 1 in the periphery and CNS.6 Employing biochemical methods, Spano7 and Kebabian8 identified two DRs, both G-protein-coupled receptors (GPCRs) or seven transmembrane receptors (7TMRs), coined D1-like and D2-like receptors. D1-like receptors stimulate adenyl cyclase (AC) and phospholipase C through Gαs to increase cAMP (Figure 1). D2-like receptors inhibit AC through Gαi/o to not only decrease cAMP but also stimulate glycogen synthase kinse 3β (GSK-3β) and potassium channels while inhibiting calcium currents.1−4,6−8 In the 1980s and 1990s, gene cloning technology found five distinct DRs, named D1−D5, which were divided into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4).1−4,6−9 D1 and D5 are characterized as having short intracellular loop 3 (i3) and long terminal carboxy tails; in contrast, D2, D3, and D4 possess long i3s and short terminal carboxy tails.1−4,6−9 The i3 loop is key © 2017 American Chemical Society

Figure 1. Cartoon of the structure and signaling of the dopamine receptor family.

for interaction of the DR with the G protein, and the genes of the D2-like receptors possess significant polymorphisms in this region. For example, the D2 receptor exists as both D2 short Received: January 29, 2017 Published: May 10, 2017 7233

DOI: 10.1021/acs.jmedchem.7b00151 J. Med. Chem. 2017, 60, 7233−7243

Journal of Medicinal Chemistry

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Figure 2. Structures and DR activities of the atypical antipsychotic clozapine (2), the D4-preferring antagonist 3, and the classical typical antipsychotic agent haloperidol (4).

cellular localization of D4 receptors with important functional significance, and these neurons project to the striatum.19 In addition, this report indicates that activation of the D4 receptors inhibits corticostriatal glutamatergic transmission.19 Due to this localization, the therapeutic role of D4 in SUD and L-DOPAinduced dyskinesias is more compelling.19 Interestingly, studies have shown that D4 agonists improve retinal and visual function.20 The ability of GPCRs to form functional heterodimers is a hot topic in drug discovery, with heterodimers displaying unique and divergent pharmacology as compared to the classical homodimer congeners.2,21−23 The D4 receptor (D4.2, D4.4, and to a lesser extent D4.7) has been shown to associate with both D2S and D2L to form heterodimers, which can potentiate D4 activation of MAPK.2,22,23 In addition, D4 has been shown to form a competent heterodimer with the β1 adrenergic receptor as well.23−26 However, selective ligands that discriminate between homo- and heterodimers are required in order to understand the therapeutic value or adverse effect liability of these novel molecular constructs, and existing D4 and D2 ligands have not been systematically evaluated against the D2/D4 heterodimers. Without question, this will be an exciting area of research in the coming years. The human D4 receptor was cloned and identified in a 1991 Letters to Nature account by Van Tol and co-workers as a new DR with high affinity for the antipsychotic clozapine (2).27 The newly identified D4 had high homology with D2/3 (>40%) and similar pharmacology and thus was grouped into the D2-like family of DRs. As clozapine was unique among atypical antipsychotics in terms of efficacy in schizophrenia (especially treatment-resistant schizophrenia) with low incidence of tardive dyskinesia, the finding in this report was that the affinity of clozapine for D4 was an order of magnitude higher for D4 (Kd = 9 nM) than D2 and D3 and matches the plasma water concentration of 2 under therapeutic conditions.28,29 This report, and subsequent reports suggesting genetic associations of D4 in schizophrenic patients,16,27 launched discovery efforts to develop D4 antagonists for the treatment of schizophrenia, as a next generation “clozapine” without the agranulocytosis risk. The enthusiasm and hope for this target cannot be emphasized enough; this was an exciting time in antipsychotic drug discovery. 1.3. Discovery of 3. In 1997, just 6 years after the discovery of the D4 receptor, researchers from Merck published a series of manuscripts28,30,31 describing the discovery of a selective and CNS penetrant D4 antagonist, (3 (3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridine)), Figure 2)

(D2S) or D2 long (D2L), an extended variant with an additional 29 amino acids.1−4,6−9 The D4 receptor gene, DRD4, is highly polymorphic in humans, particularly in the region that codifies the i3 loop, with variant number of tandem repeats of 48 nucleotides, which code from 2 to 11 hexadecapeptide repeats (D4.2−D4.11).1−4,6−9 The most predominant allelic frequencies are D4.2 (∼9% of population), D4.4 (∼65% of population), and D4.7 (∼19% of population); importantly, these variations have been shown to have no impact on G protein (Gαi/o) coupling. 1−4,6−10 Overall, a diverse array of approved medications target DRs and constitute the standard of care in schizophrenia, Parkinson’s disease (PD), and numerous other diseases; however, there are very few highly selective ligands for individual DR subtypes or that possess clean ancillary pharmacology against related biogenic amine receptors (adrenergic, muscarinic, serotonin, etc.).1−4,6−9 Indeed, DRtargeting drugs are highly effective and represent an early example of the therapeutic benefit of polypharmacology in complicated diseases. However, from a basic science perspective, the lack of highly selective small molecule tools has made it challenging to truly dissect the pharmacology and therapeutic potential of activation/inhibition of individual DR subtypes and recapitulate the exciting data derived from DR (−/−) mice.11,12 In this report, we will review the historical data on D4 pharmacology and ligands and then highlight recent advancements with next generation of D4 ligands and the evolving therapeutic potential of truly selective inhibition of D4. 1.2. Dopamine D4 Receptor. The dopamine D4 receptor (D4) is encoded by the DRD4 gene, and numerous studies have associated it with psychiatric disorders (schizophrenia and bipolar disorder), addictive behaviors, PD, eating disorders (such as anorexia nervosa), impulsivity/novelty seeking, and for the D4.7 variant, attention deficit hyperactivity disorder (ADHD).1−4,11−19 However, these findings are not without controversy, and in many cases, results have not replicated or withstood further scrutiny. The strongest associations for D4 still remain for novelty seeking, substance abuse disorders (SUD), and ADHD (22% increase if carry the D 4.7 variant).1−4,11−19 In terms of expression, D4 has the lowest level of expression of the five DR subtypes; however, the predominant localization of D4 receptors in the brain is the frontal cortex (D4 receptor mRNA), as well as other areas (amygdala, hippocampus, globus palidus, substantia nigra pars compacta, and thalmus) and the periphery (retina, kidney, adrenal glands, sympathetic ganglia, blood vessels, heart, and the gastrointestinal tract).1−4,11−18 A recent report has shown that pyramidal cortical glutamatergic neurons are a main 7234



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Figure 3. Structures of select piperazine-based dopamine D4 receptor antagonists.

along with ground breaking preclinical and clinical efficacy studies. Compound 3 possessed subnanomolar binding at D4 (Ki = 0.43 nM), 5- to 20-fold higher than the typical antipsychotic haloperidol (4, Ki = 2.3 nM) or 2 (Ki = 10 nM), respectively, and was >2000-fold selective versus D1−3,5 (D1 Ki > 10 μM, D2 Ki = 960 nM, D3 Ki = 2,310 nM, D5 Ki > 10 μM). In addition, 3 counteracted dopamine-mediated inhibition of AC activation and [35S]-GTPγS binding.30 This was truly unprecedented DR subtype selectivity with an orthosteric ligand at that time; however, the arylpiperazine moiety, a known GPCR privileged structure (e.g., promiscuous chemotype), results in off-target affinity at a number of biogenic amine GPCRs (e.g., sigma (Ki = 130 nM), adrenoreceptor α2A (Ki = 170 nM), adrenoreceptor α2B (Ki = 160 nM), adrenoreceptor α2C (Ki = 230 nM), adrenoreceptor α1C (Ki = 2200 nM), adrenoreceptor α1B (Ki = 2,900 nM), serotonin 5HT2 (Ki = 200 nM), serotonin 5HT1A (Ki = 7800 nM)). The study indicated no activity at adenosine, muscarinic, neurotensin, and neurokinin receptors, but a broader ancillary pharmacology profile (binding and functional) has never been reported for 3.30 Thus, 3 is a D4 preferring ligand, with significant, potent off-target affinity, and results with 3 must be considered in this light. Compound 3 was a good in vivo tool for studies in both rats (brain/plasma partition coefficient, Kp > 10, F = 66%, and t1/2 = 2.1 h) and rhesus monkey (F = 20% and t1/2 = 2.8 h).30,31 Due to the excitement of 3 as a novel antipsychotic agent, it was tested in a number of preclinical behavioral paradigms. Unlike 2 and 4, 3 had no effect on prolactin levels and no effect on dopamine metabolism in several brain regions. While it dosedependently (3−30 mg/kg, po) reversed mescaline-induced head twitch, it did not exhibit a neuroleptic/antipsychotic-like profile in rodents (no effect in amphetamine-induced hyperlocomotion (AHL), conditioned avoidance responding (CAR), prepulse inhibition (PPI), apomorphine-induced stereotypy assays) and at high doses (100 mg/kg) induced extrapyramidal side effects (EPS). In naive rhesus monkeys, 3 reduced locomotor activity, increased PD-like behaviors, and induced sedation. Thus, inhibition of D4 did not display the same efficacy as clozapine in these assays, leading the authors to suggest that D4 was not behind the efficacy of 2.31

Also, in 1997, Merck reported on the effect of 3 in acutely psychotic inpatients with schizophrenia.28 In this trial, 38 acutely psychotic and neuroleptic responsive patients were randomized (2:1) with either 3 (n = 26, 15 mg/day) or placebo (n = 12) after a 3−5 day placebo run-in period. About a third of the patients treated with 3 discontinued the study due to insufficient therapeutic response. After 4 weeks, the brief psychotic rating scale favored placebo, and a large percentage of 3-treated patients reported worsening of symptoms. Thus, the clinicians concluded that 3 was ineffective as an antipsychotic agent for the treatment of neuroleptic responsive patients with acute schizophrenia.28 While issues could be raised regarding patient selection (should they have explored drug naive or first episode patients and/or a higher dose of 3), these combined negative preclinical and clinical disclosures with the D4preferring antagonist 3 had a major impact on interest in D4 as a target, and little attention was focused on D4 for over a decade after these publications.

2. HISTORICAL D4 RECEPTOR LIGANDS 2.1. Aryl-Linked Piperazine Analogs. Historical dopamine 4 receptor (D4R) antagonists (late-1990s onward) shared a common structural feature: a core piperazine or piperidine scaffold with aromatic rings flanking either side separated by a linker.32 Due to a similar moiety being found in other dopamine receptor ligands (basic nitrogen core scaffold), selectivity has been a challenge, although this has been overcome in some ligands via modulation of the linker length, which is generally shorter in D4R selective compounds (one to three carbons).32 All of these initial scaffolds maintained the arylpiperazine moiety but were distinct in the linker portion of the molecule (right-hand side of molecule, Figure 3, Table 1). Compounds 5 and 6 maintained the 4-chlorophenyl group and modified the benzylic heterocyclic functionality from the pyrrolo[2,3-b]pyridine of 3 to pyrazolo[1,5-a]pyridine structure.33 These compounds were rationally designed using a pharmacophore model derived from a CoMFA study.34,35 Although these compounds maintained significant potency against the D4.4 receptor, they were ∼10-fold less potent than 3. Very limited selectivity data have been published for these 7235



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Table 1. Reported Potency and Selectivity of Piperazine-Based Dopamine D4 Receptor Antagonists Ki (nM) compd

D4.4

D1

D2

D3

3, L-745,870

0.43

>10000

960

2310

5, FAUC 113

3.6

12000

5000

6, FAUC 213

2.2

5500

7, A-381393a

D4: 1.5

>8000

2S: 4300 2L: 3200 2S: 6300 2L: 3400 2L: >6000

>6000

8, PD89211 9

D4.2: 3.6 4.3

2L: >5882 413

>3030 679

10, NGD-94-1b

D4.2: 4.2 D4.4: 2.2 D4.7: 2.1

2230

8000

5-HT1A: 1365 5-HT2A: 370 α2C: 1912 >3000 nM for α1A, α2A, 5-HT1A, 5-HT2 α1A: 203 α1B: 787 α2A: 411 α2B: 368 5-HT1A: 792 5-HT2: 1678 σ1: 232 σ2: 231 M5: 964 5-HT1A: 180

5300

>3310

>2000

>3000

738

2840

411

199

240

>8378

1842 5147

2682 >2778

3000

5-HT3: 750 α2: 2520 H1: 3700 5-HT1A: 180 5-HT2A: 500 5-HT1A: 540 α1: 967 α2A: 249 α2C: 336 σ1: 1.6 5-HT1A, 134 5-HT2A, 5.8 α1, 38 α2, 181 >1600 nM for α1A, α2A, 5-HT1A, 5-HT2A, 5-HT6, H1 α1: 322

93

Ki > 2000 nM for 5-HT1B, 5-HT2C, 5-HT6, 5-HT7, σ2, α1A, α2A, H1. b1000 nM.

a

compounds. Both Abbott Laboratories36 and Pfizer37 disclosed 2-benzimidazoles as replacements for the pyrrolo[2,3-b]pyridine group (7 and 8). Compound 7 (A-381393) displayed a Ki = 1.5 nM against D4 (no subtype reported),36 whereas 8 (PD89211) had a Ki = 3.6 nM against D4.2.37 Both showed reasonable selectivity against other dopamine receptors (∼1000×) and against selected receptors, although 7 showed activity against 5-HT2A (Ki = 370 nM). Compound 9 replaced the pyrrolo[2,3-b]pyridine with a benzo[b][1,4]oxazin-3(4H)one moiety.38 This compound was far less selective against other reported dopamine receptors (∼100-fold selective vs D2

and D3); however, 9 was active in vivo in preclinical models of schizophrenia.38 Two disclosed compounds (10 and 11) replaced the aryl group with a heteroaryl group (2pyrimidine).39,40 Neurogen Corporation disclosed compound 10 (NGD 94-1) and showed that it was equipotent against three D4 isoforms (D4.2, D4.4, and D4.7) and had selectivity against the other dopamine receptors; however, it did have activity against 5-HT1A (Ki = 180 nM).39 Compound 10 was unique in that it contained a substituted imidazole core and not the bicyclic cores previously reported.39 Pfizer disclosed 11 (CP-293,019) as another unique dopamine scaffold that 7236



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Figure 4. Structures of amide-linked piperazine-based dopamine D4 receptor antagonists.

cisoid as shown in Figure 4.47 On the basis of this orientation, the group designed a set of cyclic constrained analogs with 18 being a representative example. Compound 18 was ∼15-fold more potent at D4 (Ki = 4 nM) than the acyclic 17; however, it was also more potent at D2 (Ki = 133 nM).47 From these analogs, the group then disclosed a novel and chiral indoline containing analog, 19.48 However, introduction of the chiral indoline moiety did not improve the selectivity for the D2 receptor, and thus this class of compounds is characterized as mixed D2/D4 antagonists. Much like predecessor compounds, 19 was active in preclinical animal models of schizophrenia; however, due to the significant D2 activity, it was summarized that the antipsychotic activity may be due to this versus the D4 activity.48 2.3. Piperidine-Based Analogs. In addition to the piperazine core scaffold, a number of piperidine-based D4 antagonists have been reported (Figure 5, Table 3). Merck Sharp and Dohme identified a series of piperidine-based antagonists from high-throughput screening campaign of their internal sample collection.49 The initial hits contained a piperidine pyrazole core scaffold which, after medicinal chemistry efforts, identified a piperidine isoxazole core scaffold as a D4 antagonist (20, L-741,742) but has significant activity against D3 (Ki = 480 nM).49,50 Another piperidine-based scaffold was reported by a group from the University of Liége and contained a naphthamide, 21.51 A number of positional isomers of the naphthyl group were evaluated with the 2naphthamide being the best. Compound 21 had similar potency at D4.2 and 5-HT2A (Ki = 11 and 44 nM, respectively); however, it was selective against D2L (Ki > 1000 nM).51 A similar aminopiperidine scaffold containing a pyridine moiety, presumably with the pyridine serving as a masked amide, was reported by Kula and co-workers at Harvard Medical School. Compound 22 (RBI-257) was a highly potent antagonist of D4 at subnanomolar values (Ki = 0.33 nM) and had varying selectivity against the other dopamine receptors, with significant activity at D2L and D3 (Ki = 568 and 145 nM, respectively).52 Compound 22 was also highly active at σ1,2 receptors (Ki = 82 nM), again highlighting the nonselective nature of the piperidine scaffold, much like the piperazine compounds.32,52 Due to the promiscuous nature of the piperazine and piperidine scaffolds, the identification of alternative moieties was initiated and some of those results are listed below. 2.4. Morpholine-Based Analogs. Although the majority of the historical D4 antagonist ligands were based on either a

contains a central octahydro-2H-pyrido[1,2-a]pyrazine scaffold.40 In addition, 11 contains a phenoxymethyl group, a group that is incorporated in the morpholine scaffolds (vide infra). Compound 11 is a potent antagonist of D4.4 with Ki = 3.4 nM; however, it showed activity against both 5-HT1A and 5-HT2A (Ki = 180 and 500 nM, respectively).40 In addition, 11 in vivo inhibited the hyperactivity produced by apomorphine, a preclinical behavioral model of schizophrenia.40 Another compound with a novel benzoindane moiety, 12 (S 18126), was discovered at Servier and reported in 1998.41 Much like the other piperazine-based antagonists, 12 was potent against D4.4 (Ki = 2.4 nM) but possessed varying selectivity against other receptors (α2A, Ki = 249 nM) but significant activity against σ1 (Ki = 1.6 nM). Additional D4 antagonists were reported that extended the linker to a two-carbon spacer (13−15). Compound 13 (PNU-96415E) contains an isochromane structure and is a potent antagonist of D4 (Ki = 3.0 nM) and 5-HT2A (Ki = 5.8 nM) and was active in vivo.42 Compound 14 (PD-168568) contains an isoindolinone and is selective for the D4 receptor versus D2 and D3, although no other selectivity data are given.43 Compound 15 (U-101387, sonepiprazole), another isochromane containing structure, was potent and selective for the D4 receptor.44 Compound 15, like 3, was evaluated in a placebo-controlled clinical trial for schizophrenia, and like 3, 15 showed no benefits in the clinical trial.45 Lastly, a three-carbon spacer was introduced containing a chiral cyclopropane, 16, by Neurogen Corporation.46 However, this compound was not selective for D4 and was characterized as a D2/D4 mixed antagonist.46 2.2. Acetamide-Linked Piperazine Analogs. Another set of piperazine-based antagonists from Neurogen Corporation contain a substituted benzylic group along with an acetamide functionality (17−19, Figure 4, Table 2). The secondary Table 2. Reported Potency and Selectivity of Piperazine Acetamide Dopamine D4 Receptor Antagonists Ki (nM) compd

D4

D2

other

17 18 19

59 4 2

>1000 133 113

α1: >10000 α1: 2003 α1: 1118

acetamide 17 was designed and had moderate potency at D4 (Ki = 59 nM) but was selective for D2, and molecular modeling studies indicated that the most favorable orientation was the

Figure 5. Structures of select piperidine-based dopamine D4 receptor antagonists. 7237



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Table 3. Reported Potency and Selectivity of Piperidine-Based Dopamine D4 Receptor Antagonists Ki (nM) compd

D4

20, L-741,742 21 22, RBI-257

2.5 D4.2: 11 0.33

D1

D2

D3 480

2830

>1700 2L: >1000 2L: 568

Table 5. Reported Potency and Selectivity of Newly Reported Dopamine D4 Receptor Antagonists Ki (nM)

Table 4. Reported Potency and Selectivity of Historical Morpholine-Based Dopamine D4 Receptor Antagonists Ki (nM) D4

D2

D3

6.2 5.6 2.8 4.9

1300 400 133

3210 1480

5−HT2A: 44 α1: 1118 σ1,2: 82.1 5-HT2A: 273 5-HTT: 207

>10000

3. NEXT GENERATION D4 RECEPTOR LIGANDS Due, in part, to the clinical failures of 3 and 15 (sonepiprazole), interest in the D4 receptor waned significantly in the mid-late 2000s and into the early 2010s. In 2012, the Vanderbilt group published a synthetic methodology procedure for the synthesis of chiral morpholines and piperazines.56 Having this novel methodology at their disposal, the group synthesized a chiral morpholine compound that had been reported in the patent literature as a racemic mixture, (rac)-27 (Figure 7, Table 5).57

Figure 6. Structures of historical morpholine-based dopamine D4 receptor antagonists.

23 24 25 26

145

other

they showed the racemic 1,4-oxazepane scaffold, 26, was also a potent D4 antagonist (Ki = 4.9 nM).54 They also utilized a 3DQSAR approach to better understand the SAR using the GRID/GOLPE methodology.55 Unfortunately, no selectivity data are reported for these compounds.

piperazine or piperidine core scaffold, work was being conducted to find alternative scaffolds. One such effort was from the Merck Sharp and Dohme laboratories looking for isosteric alternatives to the previous scaffolds. As such, they identified the racemic morpholine scaffold as a selective D4 antagonist (Figure 6, Table 4).53 The group identified and

compd

D5

compd

D4.4

D1

D2

D3

D5

(R)-27 (R)-28

70 36

>100000 >20000

15700 >20000

ND >20000

(S)-29

14.3

2 for most analogs tested. In addition to the morpholine analogs, in 2016, the Vanderbilt group also revealed a novel, chiral 4,4-gemdifluoropiperidine scaffold with high potency and selectivity.60 The group identified (R)-30 as key compound which is highly potent and selective for D4.4 (Ki = 5.8 nM, 5), due the introduction of the difluoropiperidine moiety. Lastly, a recent publication from a group at the National Institute of Drug Abuse (NIDA) identified a novel imidazoline nucleus, 31.61 The group utilized binding studies to show the compounds are selective for D4 over D2 and D3; however, no further selectivity was reported.61 Although these compounds are not as potent as other reported scaffolds, this represents a novel core structure for further refinement.

4. NEW THERAPEUTIC POTENTIAL OF MODULATING D4 The D4 receptor and selective antagonists thereof have garnered renewed enthusiasm over the past several years, and this has carried the field beyond the previous interest as antipsychotics. However, as with the historical excitement, some of the new therapeutic potential will only be realized with the discovery of more selective ligands. The three main areas of interest for the D4 receptor that will be discussed are substance use disorders (SUDs), Parkinson’s disease, L-DOPA-induced dyskinesias (PD-LIDs), and cancer. 4.1. D4 Antagonists and Addiction. The first area of interest is the association of the dopamine D4 receptors and psychostimulant addiction.13,62−64 There are ∼2M current cocaine users in the U.S. with young adults being the largest population of users, according to the National Survey on Drug Use and Health (NSDUH). And at present, there are no approved treatments for cocaine addiction. Previous studies examined the D1, D2, and D3 receptor antagonists which have contributed to a better understanding of the neurocircuitry changes associated with addiction; however, these have not yielded a treatment.62 More recently, emerging data suggest that D4 receptors facilitate some of the effects of psychostimulants with high abuse potential.13,65−67 Genetic association studies have historically provided compelling data (however, some of these data have been called into question),68,69 but recent developments with genetically modified mice have helped better understand the association of D4 and addiction, although there still remains questions regarding these mutant mice.13,62,65,70,71 Although there is compelling evidence associated with D4 and addiction, most of the work reported thus far utilizes less than ideal “selective” ligands, such as buspirone and others; thus the identification of more selective 7239



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over the past 20 years, starting from a hotbed of activity due to the excitement surrounding its potential as a novel antipsychotic therapy to the unfortunate clinical failures of the lead compounds in the late 1900s to the lull of activity in the early to mid-2000s to the now re-engergized interest in the optimization and identification of new selective antagonists. Few receptors have had this type of activity. However, with major unmet medical needs still present (substance abuse) and the emergence of new potential therapeutic targets from CNS (PD-LIDs) to cancer, the future of D4 antagonist development appears to be trending upward. However, significant work still remains as selectivity against the other dopamine receptors as well broad panel selectivity is still a hurdle as well as optimization of pharmacokinetics; much work is still required.

scores” into a global rating scale. Compounds (S)-29 and 3 were both evaluated in this new model, and (S)-29 produced a dose-dependent reduction in both basic and amplitude AIM scores, and global AIM scores were markedly improved in both doses (10 and 20 mg/kg).88 Compound (S)-29 produced a 59% and 71% reduction, respectively, compared to vehicle at the doses evaluated which was significantly more effective than 3 (1 mg/kg (12%) and 3 mg/kg (22%)),88 with no marked effects on motor depression. Although more work will be needed, the use of D4 antagonists for potential treatment of PD-LIDs remains a very promising area of research and the use of more highly optimized ligands will be invaluable going forward. 4.3. D4 Antagonists and Cancer. Recent studies implicated the D4 receptor as a potential anticancer target. The first publication, in 2012, centered around a screening campaign to identify compounds that selectively target cancer stem cells (CSCs).89 Targeting CSCs to induce either differentiation or apoptosis remains an appealing approach for therapeutic intervention. From the high-throughput screen (devised to screen for compounds that differentiate CSC-like cells) the authors identified thioridazine as the most promising hit.89 The authors further evaluated thioridazine and found that it reduced the ability of human acute myeloid leukemia (AML) samples to proliferate and self-renew. AML is a cancer of the myeloid blood cells and is the most common acute leukemia, even though it is a relatively rare disease. Thioridazine is a highly potent D4 antagonist (Ki = 1.5 nM); however, it also is active against all of the dopamine receptors, along with a multitude of other receptors. But the authors showed that dopamine receptors were upregulated in human AML samples, and higher expression was correlated to worse clinical outcomes.89 Even though thioridazine is not a selective D4 antagonist, this is a promising avenue for exploration using the newer, more selective D4 antagonists in order to tease out the individual receptor contributions. A more recent publication reported that inhibition of D4 receptor disrupts the autophagy−lysosomal pathway of glioblastoma neural stem cells (GNS) leading to apoptosis.90 Glioblastoma (GBM) is an aggressive cancer that begins within the brain and has proven to be resistant to treatment. GBM growth is originated and sustained by subpopulations of tumorigenic cells, termed GBM stem cells, which contribute to tumor progression and resistance.90 The authors established proliferation assays of three different human cell types, GNS, fetal NS, and the BJ fibroblast cell line, and then screened a library of 680 neuroactive compounds.90 From this screen, they determined that dopaminergic, serotonergic, and cholinergic pathways affect CNS survival and that GBM tumors and patient-derived GNS express functional D4 receptor. In addition, they show, using 3, that D4 antagonists selectively target GNS growth in vitro and in vivo and that GNS are vulnerable to D4-mediated disruption of the autophagy− lysosomal pathway.90 This is a particular exciting result as most D4 antagonists have been developed for disorders of the CNS and thus provide the research community with brainpenetrant tool compounds Again, further optimization of potency, selectivity, and PK properties will be highly beneficial to this and other disease pathways.

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AUTHOR INFORMATION

Corresponding Authors

*C.W.L.: e-mail, [email protected]; phone, 615322-8700; fax, 615-343-3088. *C.R.H.: e-mail, [email protected]; phone, 402-5599729; fax: 402-559-5643. ORCID

Craig W. Lindsley: 0000-0003-0168-1445 Notes

The authors declare no competing financial interest. Biographies Craig W. Lindsley is William K. Warren Jr. Chair in Medicine, Professor of Pharmacology and Chemistry and Director of Medicinal Chemistry for the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) at Vanderbilt University. Craig received his doctorate in 1996 from the University of Californa, Santa Barbara, and pursued postdoctoral studies at Harvard University. In 2001, Craig moved to Merck & Co., Inc., and developed a streamlined approach for lead optimization, resulting in delivery of six preclinical candidates. He also provided preclinical proof-of-concept for the first isoenzyme selective, allosteric AKT kinase inhibitors, the first mGlu5 and M1 PAMs. The VCNDD has licensed eight programs to pharma partners and holds an open IND for their M1 P PAM. He is also the founding Editor-in-Chief of ACS Chemical Neuroscience. Corey R. Hopkins is Associate Professor in the Department of Pharmaceutical Sciences in the School of Pharmacy at the University of Nebraska Medical Center. Corey completed his doctorate in 2002 at the University of Pittsburgh on the total synthesis of the naphthyridinomycin/bioxalomycin class of compounds. He also developed novel ring expansion methodology to make pharmacophore analogs of dnacin. Corey moved to Aventis Pharmaceuticals in 2001 and later became Senior Research Investigator in Medicinal Chemistry. In 2008, Corey accepted a Research Assistant Professor position in the Department of Pharmacology and served as Associate Director of Medicinal Chemistry for the Vanderbilt Center for Neuroscience Drug Discovery where he led the chemistry efforts on multiple projects. In the summer of 2016, he moved his laboratory to UNMC.

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ACKNOWLEDGMENTS The authors acknowledge funding from the Michael J. Fox Foundation for Parkinson’s Research (MJFF Grant 10000, C.R.H.) and the William K. Warren Foundation.

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5. CONCLUSION The interest in the dopamine receptor 4 (D4R) as a therapeutically relevant target has seen a roller coaster ride

ABBREVIATIONS USED CNS, central nervous system; GPCR, G-protein-coupled receptor; D4, dopamine receptor subtype 4; PD, Parkinson’s 7240



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disease; DR, dopamine receptor; AC, adenyl cyclase; SUD, substance abuse disorder; ADHD, attention hyperactivity disorder

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