Interactions of Nitrogen-Containing Xenobiotics with Monoamine

SEPTEMBER 2001 VOLUME 14, NUMBER 9 © Copyright 2001 by the American Chemical Society

Invited Review Interactions of Nitrogen-Containing Xenobiotics with Monoamine Oxidase (MAO) Isozymes A and B: SAR Studies on MAO Substrates and Inhibitors Amit S. Kalgutkar,*,† Deepak K. Dalvie,† Neal Castagnoli, Jr.,‡ and Timothy J. Taylor† Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut 06340, and Peters Center for the Study of Parkinson's Disease, Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 Received April 11, 2001

Contents 1. 2. 3. 4. 5. 6.

Introduction Tissue Distribution Structure-Function Catalysis Acyclic Amines as MAO Substrates Examples of Acyclic Amine-Containing Drugs as MAO Substrates 6.1. Citalopram 6.2. Triptan Class of Antimigraine Agents 6.3. Milacemide 7. Cyclic Tertiary Amines as MAO Substrates 7.1. MPTP and Analogues 7.2. Tetrahydro-β-carbolines and Tetrahydroisoquinolines 7.3. Haloperidol 8. Active Site Models for Monamine Oxidases 9. MAO Inhibition 10. Reversible MAOIs 10.1. R-Methylmonoamines

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10.2. Aryloxazolidinones and Related Heterocycles 10.3. Hydroquinone Derivatives 10.4. 5H-Indeno[1,2-c]pyridazines 10.5. Coumarins 10.6. Tricyclics 10.7. MAOIs in Cigarette Smoke 10.8. MPTP and Its Metabolites 10.9. Indoles 10.10. Isoquinolines 10.11. Moclobemide and Related Analogues 10.12. Miscellaneous 11. Irreversible MAOIs 12. Concluding Remarks 13. References

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1. Introduction The monoamine oxidases1 (MAO) A and B (EC 1.4.3.4; amine-oxygen oxidoreductases) are flavoenzymes that * To whom correspondence should be addressed. Phone: (860) 7152433. Fax: (860) 715-4695. E-mail: [email protected]. † Pfizer Global Research and Development. ‡ Virginia Tech.

10.1021/tx010073b CCC: $20.00 © 2001 American Chemical Society Published on Web 07/20/2001

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Chem. Res. Toxicol., Vol. 14, No. 9, 2001 Chart 1

catalyze the oxidation of structurally diverse amines including the neurotransmitters dopamine, norephinephrine, serotonin (5-HT), tyramine, 2-phenylethylamine (PEA), and exogenous amines including the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1) (Chart 1) (1-5). The finding that several drugs are MAO substrates raises the possibility of serious drug-drug interactions that may be a source of side effects (6-10). MAO inhibitors have been targets for therapeutic agents for many years. However, inhibition and modulation of this enzyme system can result in undesirable elevations in plasma concentrations of MAO substrates and, in some instances, cytochrome P450 substrates (11). The recent development of a new generation of highly selective, reversible MAO inhibitors has led to a renewed interest in the therapeutic potential of these compounds. The primary objective of this review is to summarize the interactions of amine-containing xenobiotics with MAO, with particular emphasis on the structure-activity requirements for substrate and inhibitors. MAO is an integral protein of the mitochondrial outer membrane. Two isozymes, termed MAO-A and MAO-B, are known. These isozymes are conveniently distinguished by their differences in substrate and inhibitor selectivities (12-15). MAO-A is inhibited by low concentrations of clorgyline (2) (see Chart 1) and preferentially catalyzes the oxidation of 5-HT and norephinephrine; MAO-B selectively catalyzes the oxidation of PEA and benzylamine and is inhibited by nanomolar concentrations of (R)-deprenyl (3). Tyramine, dopamine, and tryptamine appear to be substrates for both subtypes.

2. Tissue Distribution Definitive evidence that the MAO-A and MAO-B are two distinct proteins has been established by the isolation of the cDNAs that encode for each form from human, 1Abbreviations: MAO, monoamine oxidase (EC 1.4.3.4; amineoxygen oxidoreductase); PEA, 2-phenylethylamine; 5-HT, serotonin; I2-BS, imidazoline-binding site; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; MPDP+, 1-methyl-4-phenyl-2,3-dihydropyridinium; MPP+, 1-methyl-4-phenylpyridinium; 7-NI, 7-nitroindazole; SAR, structure-activity relationship; TN, turnover number from double reciprocal plots expressed as micromoles of substrate oxidized per minute per micromole of enzyme; Km, Michaelis constant (µM); MAOI, monoamine oxidase inhibitor; PET, positron emission tomography; FAD, flavinadenine dinucleotide; HP, haloperidol (81); HPTP, tetrahydropyridine derivative (82) of haloperidol; HPP+ pyridinium metabolite (84) of HPTP.

bovine, and rat tissues and from the deduced amino acid sequences (17-22). Although MAO is expressed in most mammalian tissues, species dependent differences in MAO activity have been observed by studying the inhibitory effects of clorgyline, (R)-deprenyl, and the mixed inhibitor pargyline (4) (see Chart 1) on the oxidation of MAO substrates (23-25). Species-specific differences in MAO-B inhibition by oxadiazolones, oxadiazolethiones, and β-aminoamides have also been described (26, 27). More recently, Inoue and co-workers have characterized species and organ differences in enzyme activity by studying the rates of R-carbon oxidation of MPTP and analogues in the brain and liver mitochondria of rabbits, dogs, monkeys, and baboons (28). The most significant finding is the greater similarity in MAO activity profiles in humans versus rodents compared to humans versus subhuman primates. In humans, most tissues, except the blood platelets (MAO-B), express both isozymes (29). The highest MAO levels are present in the liver and the placenta and the lowest in spleen. The preponderance of MAO-A in human placenta, lung and the small intestine and MAO-B in the myocardium has been established (30-32). Rodriguez and co-workers have studied the localization of MAO-A and -B in human pancreas, thyroid, and the adrenal glands using monoclonal antihuman MAO-A (6G11/E1) and anti-human MAO-B (3F12/ G10/2E3) antibodies (33). The results of these studies indicate that the exocrine pancreas and the thyroid and adrenal glands show a widespread distribution of MAOA, whereas MAO-B is present only in centroacinar cells and epithelial cells of pancreatic ducts. MAO isozymes also are present in most areas of the human brain. MAO-B appears to be predominantly localized in serotonergic neurons whereas dopaminergic neurons contain MAO-A (34-37).

3. Structure-Function Structural aspects of MAO-A and MAO-B in relationship to their primary sequence and secondary and threedimensional geometries have been reviewed (38). Primary structures deduced from cDNA clones suggest that the two isozymes consists of 526 (MAO-A) and 520 (MAO-B) amino acid residues with molecular weights of 59 700 and 58 800, respectively, and have 70% sequence identity (19, 39-41). The secondary structures of human MAO-A and bovine MAO-B have been investigated by Fourier Trans-

Invited Review

form Attenuated Total Reflection Spectroscopy (FTIR ATR). The experimental results indicate a distinct folding and molecular specificity of the two MAO subtypes (42). Four highly conserved regions in the MAO isozymes have been identified. These are (1) an ADP-binding unit (residues 6-43); (2) a putative substrate binding domain (residues 178-221); (3) a site for the FAD covalent attachment (residues 350-458); and (4) a C-terminus region (residues 491-511) predicted to form a transmembrane-associated R-helix (38, 43). A combination of affinity labeling experiments using the pseudosubstrate inhibitor N-[2-aminoethyl]-5-chloro-2-pyridinecarboxamide (lazabemide, 5) and site-directed mutagenesis studies has provided evidence that amino acid residues His382 and Thr158 in MAO-B are essential for the catalysis whereas Phe208 in MAO-A and Ile199 in MAO-B are key determinants of substrate specificity (44-47). There is strong evidence that two cysteine residues also are present in the active site of MAO and may be involved in catalysis (48, 49). Sablin and Ramsay have shown that both isozymes contain a redox-active disulfide in the catalytic active site suggesting that the MAOs may represent a novel type of a disulfide oxidoreductase (50). Detailed examination of several chimeric MAO forms made by progressively moving and replacing discrete regions of one form with the regions of the other form have been reported (51-53). The studies have aided in the identification of various regions in the proteins that are responsible for the substrate and inhibitor recognition. All chimeric enzymes that retain the amino terminus of MAO-A possess type A substrate selectivity, indicating that this region is responsible for binding 5-HT. Similarly, the middle and the amino terminal portions in MAO-B are thought to be responsible in the binding of MAO-B substrates (53). Recent studies also have revealed that both isozymes possess an imidazoline-binding site (I2-BS) that recognizes imidazolines, guanidiniums, and related structural analogues (54-57). The strong inhibitory effects of I2selective imidazoline ligands such as antazoline (6), idazoxan (7), and cirazoline (8) (see Chart 1) confirm the existence of the I2-BS as a regulatory site on MAO (58, 59). Furthermore, the I2 sequence purified from rabbit kidney mitochondria displays ∼86% similarity with the corresponding region of human, rat, and bovine MAO-A and B (60). Studies with R-adrenoceptor ligands including derivatives of imidazoline, imidazole and guanidine, suggest that the I2-BS in MAO-B is distinct from the catalytic domain and is not associated with the FAD prosthetic group (54, 61-63). However, it encompasses a region (amino acids K149-M222 in human MAO-B) involved in substrate processing/selectivity as indicated by studies on chimeric MAO-A/B enzymes and sitedirected MAO mutants. It also appears to be involved in the inhibition of enzyme activity (47, 51, 53, 60). For instance, the Tyr158Ala MAO-B mutant is catalytically inactive and an Ile199Phe conversion results in isozyme switching relative to substrate selectivity and inhibitor sensitivity (47, 64, 65). A series of phenoxy-substituted methylimidazoline derivatives has been synthesized and used to define the ligand recognition properties of I2BS in MAO-B and its role in catalysis (66). Contrary to earlier reports, a recent publication by Parini et al. indicates that the I2-BS, as identified by high affinity [3H]idazoxan binding, is in fact located exclusively on MAO-B (67). Thus, [3H]idazoxan binding is completely

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abolished in both liver and brain tissue derived from MAO-B-deficient mice, two organs that are supposed to contain a heterogeneous population of I2-BS. In contrast, no difference in [3H]idazoxan binding in MAO-A-deficient mice compared with the wild-type parent strain is observed. These new findings suggest that the imidazoline-binding site in MAO-A may not belong to the I2-BS subtype and that MAO-B deficient mice may represent an ideal model to investigate the pharmacological functions of I2-BS. Overall, identification of an I2-BS exclusive to MAO-B and which is distinct from the domain interacting with known mechanism-based inactivators of MAO-B may provide an alternate strategy to develop selective MAO-B inhibitors. It has been known for quite some time that a flavinadenine dinucelotide (FAD) moiety (9) is covalently linked to Cys406 and Cys397 in human MAO-A and -B, respectively, via the 8R-methyl group of the isoalloxazine ring of FAD (17, 68, 69). Site-directed mutagenesis of the cysteine residue in the two isozymes demonstrates that Cys397 is essential for the catalytic activity of MAO-B but not MAO-A since the Cys406Ala MAO-A mutant exhibits ∼40-60% catalytic activity (48, 70). Edmondson et al. have characterized the effect of riboflavin analogues on the catalytic activity of the Cys406Ala mutant and have demonstrated new insights in the binding of flavin to MAO-A and into the possible roles of the covalent linkage of the flavin to the protein (71). Miller and Edmondson also have studied the relationship between catalysis and riboflavin structure in MAO-A and -B (72). Flavin analogues with a variety of substituents are found to confer catalytic activity. The selectivities of MAO-A and B are similar although 8R-methylation of the flavin results in a higher level of catalytic activity for MAO-B than for MAO-A. In addition to the covalent binding site, two noncovalent flavin binding regions have been identified in MAO-B (residues 6-34 and 39-46) (73-75). Sitedirected mutagenesis experiments have shown that Glu34, Arg42, Tyr44, and Tyr45 are important amino acid residues that engage in initial noncovalent interactions with FAD and generation of catalytic activity.

4. Catalysis Although both isozymes differ in their substrate and inhibitor selectivities, they both are able to catalyze the oxidation of 1°, 2°, and 3° amines. Ramsay et al. has reviewed the possible involvement of substrates in the regulation of MAO catalytic activity (76). The FAD moiety is functional in the oxidative deamination of amine substrates and is involved in the transfer of electrons from the amine nitrogen to oxygen (Scheme 1). In the process, the amine 11 is converted to an protonated iminium species 12 that is released from the active site and hydrolyzed to the corresponding aldehyde 13 and ammonium ion. The most important structural feature for MAO substrate properties is the presence of the two hydrogen atoms on the R-carbon in amines. Furthermore, Yu and co-workers have demonstrated that both MAO isozymes exhibit the same stereospecificity by abstracting the pro-R-hydrogen exclusively from the prochiral methylene group in amine substrates (77). Three pathways for the MAO-catalyzed oxidation of amines have been described. These are (1) the single electron transfer (SET) pathway first proposed by Silverman (78, 79), (2) a hydrogen atom transfer (HAT)

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Chem. Res. Toxicol., Vol. 14, No. 9, 2001 Scheme 1. Oxidation of Amines by MAO-Bound FAD

Scheme 2. Radical Pathways Proposed for the MAO-B-Catalyzed Oxidation of Amines

pathway as proposed by Walker and Edmondson (80), and (3) a nucleophilic or polar mechanism as proposed by Kim and co-workers (81, 82). The SET pathway (Scheme 2) proceeds by an initial electron-transfer step from the nitrogen lone pair of the amine substrate 11 resulting in the aminyl radical cation (14) and flavin semiquinone (Fl•-). Proton loss from 14 results in the carbon-centered radical 15 which can transfer the second electron to the flavin semiquinone (pathway a) to yield the iminium species (12) and reduced flavin (FADH2). Direct R-hydrogen atom loss from the radical cation 14 leading to 12 also has been considered (83). Alternatively, the carbon-centered radical 15 could undergo radical combination with an active site radical (pathway c) to give a covalent adduct 16 which could yield the iminium species 12 by β-elimination. Experimental evidence supporting the SET pathway for MAO-B-catalyzed reactions is derived in part from the mechanism-based inactivator properties of cyclopropylamines (84, 85) and cyclobutylamines (86). Evidence against the SET pathway in the MAO-catalyzed reaction includes the inability to detect radical cation intermediates by rapid-scan, stopped flow, and magnetic field techniques (87). Energy calculations also indicate a higher value for ∆Gelectron transfer vs ∆G( for the ratelimiting reduction of MAO by amine substrates under anaerobic conditions (80). Furthermore, the substrate properties, as opposed to the expected inactivator properties, of certain 4-substituted 1-cyclopropyl-1,2,3,6-tet-

rahydropyridinyl derivatives suggest that aminyl radical cations may not be obligatory intermediates in the MAOcatalyzed oxidation of cyclic tertiary allylamines (88-90). In light of these results, some investigators have considered HAT as an alternate catalytic pathway since it does not pass through the radical cation intermediate (see Scheme 2). This mechanism involves a rate-limiting H• abstraction from the R-carbon of the amine substrate 11 leading to the R-aminyl radical 15. Rapid electron transfer from the R-aminyl radical 15 results in the protonated iminium species 13 and the flavin hydroquinone (91). The presence of an ESR signal in MAO-B purified from bovine liver (92) that could be interpreted as evidence in favor of the HAT pathway has not been detected in human liver MAO-B expressed in Pichia pastoris (93). A polar mechanism also has been proposed to account for the MAO-catalyzed oxidations of primary and secondary amines (81, 82). According to this pathway, the amine substrate forms an adduct (17) with FAD (Scheme 3). Subsequent cleavage of 17 yields the iminium metabolite 12 and reduced FADH2 (18). Results from model studies with several MAO inactivators have provided additional support for this mechanism (81).

5. Acyclic Amines as MAO Substrates MAO catalyzes the oxidation of structurally diverse acyclic amines. In addition to neurotransmitters, several acetylated endogenous polyamines including N-acetylputrescine, N-acetylspermidine, and N-acetylspermine are substrates for these enzymes (see Figure 1) (94, 95). Although some of these amines are preferentially metabolized by MAO-A or MAO-B, none is a “true isozymespecific substrate”. They do, however, demonstrate different kinetic parameters. Elaborate SAR studies with arylalkylamine substrates and inhibitors suggest that MAO-A and MAO-B are efficient catalysts for amines, which bear an aryl group 1-3 carbons from the amine nitrogen. Although, 1° and

Scheme 3. Proposed Polar Pathway for the MAO-Catalyzed Oxidation of Amines

Invited Review


Figure 1. Examples of endogenous and exogenous acyclic amines as MAO substrates.

Scheme 4. MAO-Mediated Metabolism of Citalopram and Its Demethylated Metabolites in Human Liver Microsomes

2° amines are deaminated indiscriminately by both isozymes, 3° amines generally display selectivity toward one form of the enzyme (96). For instance, the MAO-Bselectivity for PEA is enhanced further by conversion to the corresponding N,N-dimethyl derivative 19 (see Figure 1) (97). Likewise, analysis of tryptamine analogues (see Figure 1) as MAO-A and -B substrates in rat liver mitochondria (98) reveals that N-methylation of the non-

selective MAO substrate tryptamine (20) results in the 2° amine 21, a selective MAO-A substrate. In contrast, N,N-dimethylation of tryptamine generates the 3° amine 22 that demonstrates weak but selective MAO-B substrate properties. In addition to an amine-binding site, the MAOs also appear to possess a hydrophobic site that binds the aromatic residue of substrates. The selectivity of PEA for MAO-B and 5-HT for MAO-A suggest consid-

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Chem. Res. Toxicol., Vol. 14, No. 9, 2001 Scheme 5. MAO-A-Catalyzed Oxidation of the Antimigraine Drugs, Sumatriptan, Rizatriptan and Zolmitriptan

erable differences in these regions of the proteins. Besides arylalkylamines, MAO also catalyzes the oxidation of simple aliphatic alkylamines (99). Thus, amines tethered to medium length alkyl chains (C5-C10) are excellent MAO substrates. On the other hand, amines tethered to short chain alkyl groups (C1-C4) or alkyl groups with chain lengths longer than C10 are poor MAO substrates. Analogues where the hydrogen atom on the R-carbon is substituted with a methyl group results in compounds that are devoid of MAO substrate properties. The resulting compounds, however, are reversible, competitive inhibitors as illustrated with the R- (23a) and S- (23b) enantiomers of amphetamine (see Figure 1) (77, 100). Modification of β-position also influences substrate recognition. The R-enantiomer 24a of 2-phenylethanolamine is a selective MAO-A substrate whereas both enantiomers of 2-phenylethanolamine are substrates for MAO-B (101). Overall, these observations suggest that the MAO-A active site may present steric constraints at the position corresponding to the β-carbon in arylalkylamines that do not exist for MAO-B. In contrast, MAO-B displays low affinity toward R-substituted amines as judged from the poor MAO-B substrate properties of R-methylmonoamines.

6. Examples of Acyclic Amine-Containing Drugs as MAO Substrates 6.1. Citalopram (25). Recent studies have established the MAO substrate properties of the selective serotonin reuptake inhibitor citalopram (25) (102). The clearance

of 25 is mediated principally through P450-catalyzed reactions leading to the N-desmethyl derivative 26 and the 1° amine 27 (Scheme 4). Testa et al. noted that 25, 26, and 27 undergo MAO-catalyzed oxidation in hepatic tissue to yield the corresponding aldehyde 28. Aldehyde oxidase-catalyzed oxidation of 28 yields the carboxylic acid 29. That MAO and not P450-catalyzed these oxidative deaminations was evident from the observations that the formation of 29 occurred in the absence of NADPH and was prevented following co-incubation with MAO-A and -B inhibitors. The subsequent involvement of aldehyde oxidase was evident from the observation that menadione, an aldehyde oxidase inhibitor, prevented further metabolism of 28. Although the extent to which MAO participates in the clearance of citalopram in vivo is not clear, several cases of the “serotonin syndrome” have been reported following overdoses of citalopram when given with the selective MAO-A inhibitor moclobemide. It is tempting to speculate that MAO inhibitors may enhance the citalopram-induced side effects by inhibiting its metabolism. 6.2. Triptan Class of Antimigraine Agents. MAO plays a dominant role in the clearance of the triptan class of antimigraine drugs. This class of compounds constitutes novel and highly selective 5-HT receptor agonists that are used in the acute, oral treatment of migraine and cluster headaches. Members of this group of drugs include acyclic 3° amines such as sumatriptan [IMIGRAN, IMITREX (30)], zolmitriptan [ZOMIG (31)] and rizatriptan [MAXALT (32)] and cyclic 3° amines such as

Invited Review


Scheme 6. MAO-B-Catalyzed Metabolism of the Anticonvulsant Drug, Milacemide

eletriptan (33) and naratriptan (34) (103-107). MAO-A is the principal enzyme responsible for the clearance of sumatriptan (30) (108). Oxidative deamination of sumatriptan leading to the corresponding carboxylic acid 35 constitutes the only phase I metabolic pathway identified in man. The involvement of MAO has been clearly demonstrated by using clorgyline, which prevents the formation of both 35 and the 1° alcohol 36 (Scheme 5). Likewise, rizatriptan (32) undergoes the MAO-catalyzed oxidative pathway leading to indoleacetic acid metabolite 37 in humans (109). Following intravenous or oral administration of [14C]rizatriptan, 37 is the major metabolite detected in human urine (35-57% of the dose) (see Scheme 6). The structurally related zolmitriptan (31) is cleared in humans primarily by metabolism mediated by P450 1A2 (110). P450 1A2 catalyzes the N-demethylation and N-oxidation of zolmitriptan to 38 and 39, respectively. Compound 38 undergoes selective MAO-Acatalyzed oxidation leading to the indole acetic acid metabolite 40 (see Scheme 5). Since the in vivo clearance of these compounds is primarily dependent on metabolism, interactions with drugs that induce or inhibit P450 1A2 or MAO-A are possible. Furthermore, moclobemide, a selective MAO-A inhibitor, produces a 3-fold increase in the area under the curve of the N-desmethyl metabolite 38 when co-administered with zolmitriptan. In contrast, moclobemide has relatively little effect on the pharmacokinetics of zolmitriptan (111). Despite their structural similarity to Sumatriptan, zolmitriptan, and rizatriptan, the cyclic 3° amines, eletriptan and naratriptan (see Scheme 5) are not MAO substrates. 6.3. Milacemide (41). Acute administration of the anticonvulsant drug milacemide (41) to rats leads to the excretion of glycinamide (43) in the urine. Oral administration of milacemide to rats results in increased glycine concentrations in various regions of the rat brain (112, 113). These observations suggested that milacemide acts as a precursor of glycine in the brain, a property which may account for its anticonvulsant actions. That MAO-B is responsible for the metabolism of milacemide in vivo was confirmed when the formation of glycine from milacemide was prevented by pretreatment with the MAO-B inhibitor (R)-deprenyl (112). Biochemical studies revealed that the formation of glycinamide (43) from milacemide is mediated through the selective MAO-Bcatalyzed oxidation at the R-methylene carbon of the pentyl group via the intermediate iminium species 42. Other oxidative products include pentanal (44) and pentanoic acid (45) (Scheme 6) (114, 115).

7. Cyclic Tertiary Amines as MAO Substrates 7.1. MPTP and Analogues. Extensive metabolic, biochemical, and toxicological studies have established that the neurodegenerative properties of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1) (Scheme 7) are mediated by MAO-B (116-118). The cascade of events leading to MPTPs selective destruction of nigrostriatal dopaminer-

Scheme 7. Metabolic Fate of the Nigrostriatal Neurotoxin, 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)

gic neurons can be summarized as follows. (1) Extraneuronal oxidation of MPTP generates the pyridinium species MPP+ (47) via the intermediate dihydropyridinium MPDP+ (46) (see Scheme 7) (117, 119, 120). (2) Active transport of MPP+ into dopaminergic nerve terminals by the dopamine uptake system follows (118, 121). (3) MPP+ localizes in the mitochondrial matrix where it inhibits complex I of the mitochondrial electron transport chain leading to cessation of oxidative phosphorylation and ATP depletion (122-125). MAO-B and, to a lesser extent by MAO-A, regiospecifically catalyze the C-6 (allylic) R-carbon oxidation of MPTP to the 2,3-dihydropyridinium species MPDP+ (126, 127). The neurotoxicological importance of this oxidation was demonstrated in experiments in which irreversible, selective MAO-B inhibitors protected monkeys and mice against MPTP’s neurotoxicity (128-130). MPDP+ is chemically unstable under physiological conditions. Among other oxidative pathways, it undergoes a bimolecular redox reaction with its conjugate base 48 to form stoichiometric amounts of MPTP and MPP+ (Scheme 7) (131). The principal fate of MPDP+ in brain homogenates is its further two-electron oxidation to MPP+, an event

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Figure 2. SAR studies on the substrate properties of C-4-substituted-1-methyl-1,2,3,6-tetrahydropyridinyl derivatives.

that has been implicated to be MAO-B catalyzed (132). Unpublished results from our laboratory, however, indicate that the two-electron oxidation of MPDP+ and related analogues to the respective pyridinium species occurs in the absence of the enzyme (133). In hepatic tissues, P450s catalyze the oxidative Ndemethylation and R-carbon oxidation of MPTP to generate secondary amine 49 and MPDP+ (134-137) (Scheme 7). MPDP+ is an excellent substrate for liver aldehyde oxidase, which catalyzes its conversion to the lactam 50 (138). Unlike liver homogenates, brain homogenates do not convert MPDP+ to 50, presumably because of the absence of aldehyde oxidase activity in the brain (139). Extensive structure-activity relationship (SAR) studies on MPTP analogues have been undertaken in an attempt to understand the unique structural features of these cyclic tertiary allylamines that lead to their unexpected MAO substrate properties and neurotoxicity. Critical requirements for optimal substrate properties include the unsaturation at C4-C5 and the presence of an N-methyl group (140-144). For instance, reduction of the double bond at C4-C5 abolishes MAO activity and replacement of the N-methyl group with hydrogen or higher alkyl groups dramatically reduces substrate properties (144-146). Likewise, introduction of alkyl groups in MPTP's tetrahydropyridine ring abolishes or reduces MAO-B substrate properties (146, 147). The presence of the phenyl group at C-4 also is important for MPTP's excellent MAO substrate properties. Replacement of the phenyl group with a proton gives an inactive compound (143). Introduction of substituents on the C-4 phenyl ring (C-2′, C-3′, or C-4′ positions) reveals a few general trends for substrate selectivity for the two isozymes. For instance, MAO-A selectivity increases with increasing steric bulk at C-2′ as illustrated by 2′-ethylMPTP (TN/Km ) 688 for MAO-A; TN/Km ) 295 for MAO-B) (127, 142, 148-150). Furthermore, only compounds bearing neutral C-2′ substituents function as MAO substrates; weakly acidic or basic groups at C-2′ lead to inactive compounds (151, 152). In contrast, MAO-B tolerates larger substituents at C-3′ and C-4′ than does MAO-A (153, 154).

Scheme 8. MAO-Catalyzed Oxidation of 4-Aryloxy- and 4-Arylthio-1-methyl-1,2,3,6tetrahydropyridinyl Derivatives

Separation of the phenyl and the tetrahydropyridinyl rings by various units affords a rich array of compounds that exhibit substrate properties and isozyme selectivity greater than those observed with MPTP (Figure 2). For instance, the C-4 benzyl analogue 51 is a better MAO-B substrate than is benzylamine or MPTP (126, 127, 148, 154-156). MAO-B selectivity changes in favor of MAO-A by replacement of the benzyl group with bulky aromatic groups as illustrated with the R-naphthylmethyl derivative 52 (157). Although replacement of the C-4 benzyl group with a 4-phenylethyl substituent (analogue 53) results in further increments in reactivity toward the two isozymes, introduction of branches (compound 54) or rigidity (compound 55) decreases activity (157). Furthermore, MAO-A does not discriminate in the oxidation of the trans- and cis-tetrahydrostilbazole isomers 55 and 56, respectively, but MAO-B displays stereospecific oxidation of the cis-isomer (157). Incorporation of heterocyclic groups at C-4 also affords excellent MAO substrates. Examples include the MAO-B selective C-4-indolyl- and the 3-ethylfuranyl-tetrahydropyridine derivatives 57 and 58, respectively (158-160). The 3-ethylfuranyl derivative 58 is one of the best MAO-B substrates ever described. The TN/Km of this compound is ∼100 times greater than that recorded for the unsubstituted furanyl derivative 59, suggesting a favorable interaction with a lipophilic domain in the MAO-B active site (160). All of the MPTP analogues discussed so far are metabolized to their corresponding dihydropyridinium

Invited Review

Chem. Res. Toxicol., Vol. 14, No. 9, 2001 1147 Scheme 9. Novel Prodrugs Dependent on the MAO-Catalyzed Oxidation of 4-Aryloxy-1-methyltetrahydropyridinyl Analogues

species. Neurotoxicity associated with these analogues, however, is dependent on the ease with which the intermediate dihydropyridinium species undergo further oxidation to the pyridinium species. Therefore, tetrahydropyridinyl derivatives that display greater MAO-A/-B substrate properties may not necessarily share MPTP's neurotoxic effects. This is illustrated with C-4 aryloxyor arylthio-tetrahydropyridinyl analogues such as 60 and 64. The dihydropyridinium metabolites derived from the MAO-mediated oxidation of these compounds undergo a different metabolic fate than is the case with MPTP (161). Thus, the MAO-catalyzed oxidation of 60 generates the corresponding 2,3-dihydropyridinium species 61 that undergoes spontaneous hydrolysis to afford phenol (62) and 2,3-dihydro-4-pyridone (63) (Scheme 9). Replacement of the oxygen atom in 60 with sulfur results in a compound 64 that retains excellent MAO-B substrate properties. However, the intermediate dihydropyridinium metabolite 65 derived from 64 is stable and neither hydrolytic cleavage nor further oxidation is observed as with MPDP+ (Scheme 8) (161). Although the hydrolytic stability of 65 can be rationalized in terms of the decreased electronegativity of the sulfur atom relative to the oxygen atom in 61, no obvious explanation for the oxidative stability of 65 relative to MPDP+ is apparent. The hydrolytic instability of the dihydropyridinium species derived from the C-4 aryloxy derivatives has been exploited to construct potential nitrogen-containing prodrugs. The tetrahydropyridinyl group serves as a carrier via a carbamoyl group (162, 163). Thus, the tetrahydropyridinylphosphoroamidate 66 is metabolized to the dihydropyridinium intermediate 67 that, upon hydrolysis, releases the cytotoxic phosphoramide mustard 68 (Scheme 9A). A second example is the tetrahydropyridinyl carbamate prodrug 69 that is converted to the dihydropyridinium metabolite 70 in a MAO-A selective reaction. Hydrolysis of 70 results in the carbamic acid 71 that decarboxylates to yield the potent MAO-B selective, mechanism-based inactivator (R)-nordeprenyl (72) (Scheme 9B). These examples illustrate potential opportunities in the design of proneuroprotectants utilizing insights that have been gained in studies focused on the mechanism of action of proneurotoxicants. Unlike the MAO-catalyzed metabolism of 4-aryloxyand the 4-carbamoyloxy-tetrahydropyridinyl analogues,

Scheme 10. MAO-B-catalyzed Oxidation of 4-(benzoyloxy)-1-methyl-1,2,3,6-tetrahydropyridine (73)

the MAO-B-catalyzed biotransformation of the ester derivative 4-(benzoyloxy)-1-methyl-1,2,3,6-tetrahydropyridine (73) did not generate a hydrolytically unstable metabolite. The 2,3-dihydropyridinium metabolite 74 derived from 73 was found to undergo 1,2-hydration to afford the carbinolamine 75 that spontaneously rearranged to the β-keto aldehyde 76 which, subsequently, was characterized as the pyrazole derivative 77 (Scheme 10) (164). The reason(s) for the different fate of the dihydropyridinium species derived from 73 is not apparent. One possibility could be the higher susceptibility of the ester moiety to undergo intramolecular aminolysis compared to the corresponding aryloxy or the carbamoyloxy derivatives. Overall, these results suggest that 2,3dihydropyridinium species generated from the MAOcatalyzed oxidation of MPTP and its analogues generally exist in equilibrium with the corresponding carbinolamine and ring opened aminoaldehydes. 7.2. Tetrahydro-β-carbolines and Tetrahydroisoquinolines. Since the discovery of MPTP’s neurotoxic properties, two related structural classes of endogenous compounds have drawn considerable attention as MAO substrates and inhibitors, namely tetrahydro-β-carbolines and tetrahydroisoquinolines. These compounds may be oxidized to the corresponding β-carbolinium or isoquinolinium ions, respectively, which are MPP+ analogues (165-167). Fused ring cyclic tertiary amines, that also are allylic amines, are known to possess excellent MAO

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substrate properties. For example, 2-methylisoindolines such as 78 and 1-methyl-3-pyrrolines such as 79 (see Figure 2) have TN/Km values ranging from 200 to 2000 (168). Of some interest is the requirement of an allylic (benzylic) amino functionality for all of these compounds. This feature is likely to be linked to the observed MAO substrate properties since, as discussed earlier with the tetrahydropyridine analogues, the related pyrrolidinyl analogue of 79, i.e., 80, is stable in the presence of MAOB. 7.3. Haloperidol. A related compound of interest in this context is haloperidol (81, HP), a neuroleptic agent that causes severe side effects including parkinsonism and tardive dyskinesia (169, 170). Although haloperidol and its dehydrated metabolite HPTP (82) are not MAO-B substrates, the conversion of HPTP to HPP+ (84) through the intermediate dihydropyridinium HPDP+ (83) may be catalyzed by MAO-A (171-174). Like MPP+, HPP+ is a potent inhibitor of complex I of the mitochondrial respiratory chain (175). Compromised mitochondrial energy production is a potentially important link between parkinsonism, neuroleptic disorders and MPTP-induced parkinsonism. Future studies in this area may provide insight into neurodegenerative processes and druginduced motor disorders.

8. Active Site Models for Monamine Oxidases Evaluation of the biological data on the MAO substrate properties of MPTP analogues as well as molecular modeling studies and comparative molecular field analysis (CoMFA) have identified lipophilicity as a key contributing factor to good MAO-A and MAO-B substrate behavior (176-179). In addition, Edmondson and coworkers have reported that the binding affinity of a series of benzylamine and phenylethylamine derivatives to MAO-A increases with an increase in the size of the parasubstituent on the aromatic ring. On the other hand, the hydrophobicity of the substituent facilitates binding to MAO-B (80, 180, 181). No obvious relationship between the rate of oxidation and physiochemical parameters such as dipole moment or ionization potential has been observed (178). Computational modeling studies also have provided some approximate estimates of the size and shape of molecules that display MAO substrate properties and have led to some active site models. Two key features in these models are the domains that accommodate the tetrahydropyridine ring and its C-4substituent. Both flexible (one or more sp3-hybridized atoms) and constrained (aryl) C-4-substituents may be well tolerated by MAO-A and MAO-B. The MAO-A active site appears to accommodate bulkier groups at C-4 better than does the active site of MAO-B. Only substitutions at the N-1- and C-4-positions of the tetrahydropyridine

ring are tolerated, and only small substituents can be accommodated at the N-1-position. The diminished MAO activity of the N-desmethyl MPTP analogue, however, suggests a minimum steric requirement at N-1. The observation that substitution at the C-4′-position on the phenyl ring of MPTP results in good MAO-B but not MAO-A substrates suggests that the substrate binding site along the main axis (N1-C-4-C-1′-C-4′) may be slightly longer in MAO-B. On the basis of these data, a maximum distance of 10-12 Å between the N-methyl carbon and the most distant carbon on the C-4-substituent has been suggested for optimal MAO-B substrates (178, 179). Generation of these computational models, however, is limited to a small subset of substrates and further refinement that will include more structurally diverse MAO substrates and inhibitors is awaited.

9. MAO Inhibition The past 30 years has witnessed the discovery of numerous competitive and slow, tight-binding monoamine oxidase inhibitors (MAOIs) that preferentially inhibit one isozyme over the other. MAOIs typically are classified into reversible (competitive or slow, tight-binding) or irreversible (affinity labeling agents or mechanism-based inactivators). Compounds belonging to the first generation of MAOIs were mechanism-based inactivators that acted via formation of reactive electrophilic intermediates that covalently modified the protein. Most of these compounds also inactivated the P450s, a consequence that led to hepatotoxic side effects (182-184). A second, more serious side effect with irreversible MAOIs is the occurrence of the so-called cheese effect, a phenomenon that led to severe hypertensive crises induced by elevated dietary tyramine levels resulting from MAO inhibition (185, 186). Such hepatotoxic and hypertensive liabilities led to a sharp decline in the popularity of MAOIs and to efforts directed toward the identification of reversible, isozyme-selective MAOIs.

10. Reversible MAOIs Reversible MAOIs can be subdivided further into competitive and slow, tight-binding inhibitors that can be distinguished by the kinetic model in the following equation: k1

k2

E + I {\ } (E‚I) 98 (E‚I*) k -1

According to this expression, the first step in the competitive inhibition process involves the formation of a rapidly reversible complex [E•I]. The second step, usually observed with slow, tight-binding inhibitors, involves the slow, time-dependent conversion of the [E•I] complex to an activated complex [E•I*] in which the inhibitor is bound more tightly to the enzyme resulting in a conformational change in the three-dimensional structure of the enzyme. The following is a brief description of SAR studies on diverse structural classes of competitive inhibitors, examples of which are presented in Figures 3-5. 10.1. r-Methylmonoamines. As previously described, substitution of a R-hydrogen atom in MAO substrates with a methyl group affords reversible, competitive MAOIs and, in many instances, the potency and isozyme selectivity can be further improved by enantiomeric

Invited Review


Figure 3. Structural classes of reversible MAO inhibitors.

resolution. For example, the (+)-isomer of amiflavine (85) is ∼550-fold more selective as an MAO-A inhibitor than is the (-)-isomer (187, 188). Many MAO substrates are converted into MAOIs by R-methylation and most demonstrate selective MAO-A inhibition (189). In contrast, β-methylation of MAO substrates often generates selective MAO-B inhibitors (190). Besides monomethylation, dimethylation of MAO substrates such as benzylamine results in selective MAO-A inhibitors such as the sympathomimetic amine phentermine (86) (Figure 3) (191). 10.2. Aryloxazolidinones and Related Heterocycles. The structural template for these types of compounds (Figure 3) is derived from MD 780236 (87), a mechanism-based inactivator of MAO-B (191-194). Replacement of the secondary amine functionality in MD

780236 with related bioisosteres abolishes their irreversible inactivation properties and generates slow, tightbinding MAOIs. The success of this strategy is highlighted with the discovery of the potent and selective MAO-A inhibitors cimoxatone [MD 780515 (88)] and toloxatone [Humoryl (89)] which have Ki values ranging from 0.03 to 2 µM (195-197). Toloxatone (89) is the first reversible and selective MAO-A inhibitor introduced as an antidepressant in clinical practice (197). Systematic modification of toloxatone led to the discovery of befloxatone (90), currently in phase III clinical trials for the treatment of depression, and compounds such as E2011 (91) and T-794 (92) with MAO-A to MAO-B selectivity ratios of ∼25000 (198-200). Isozyme selectivity is dramatically improved by replacing the central

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phenyl group in befloxatone (90) with larger heteroaromatic substituents as illustrated with E2011 (91) and T-794 (92) (199-202). SAR studies demonstrate the strict requirement for the R-configuration of the stereogenic center of the methoxymethyloxazolidinone moiety and a para-substituent on the aryl ring for good inhibition properties. Apart from these compounds, members of the oxazolidinone class of synthetic antibacterial agents such as linezolid (93) are also known to possess weak MAO inhibitory properties (203). No clinical evidence of adverse reactions related to this property has been reported (203). Replacement of the heterocyclic ring in aryloxazolidinones with other five- or six-membered ring systems to give oxadiazolones, oxadiazinones, or tetrazoles, reverses isozyme selectivity from MAO-A to MAO-B (204-206). Optimal structural requirements include an aromaticsubstituted heterocycle and an unsubstituted benzyloxy group in the para-position of the aromatic ring as shown with 94. Replacement of the heterocycle in 94 with an acyclic semicarbazone or acylhydrazone group generates compounds such as 95 that demonstrate potent, slow, tight-binding MAO-B inhibition with IC50 values ranging from 1 to 6.0 nM and selectivity ratios greater than 70,000 (207). 10.3. Hydroquinone Derivatives. Certain O-substitutedhydroquinone analogues such as 96 or 97 recently were reported to be reversible and selective MAO-B inhibitors (Figure 3) (208). SAR analysis revealed that the presence of electron-withdrawing groups on the 2-position of the hydroquinone ring and esterification of

the secondary alcohol moiety in 97 increases potency and selectivity. For example, the IC50 value for the inhibition of MAO-B by 98 is between 20 and 30 nM and the selectivity ratio is ∼30 000. 10.4. 5H-Indeno[1,2-c]pyridazines. Other novel heterocyclic systems with impressive MAO inhibition properties have been described as well. For instance, several 5H-indeno[1,2-c]pyridazines exemplified with 99 (Figure 3) were found to be potent, competitive and selective inhibitors of MAO-B (209-211). Three-dimensional QSAR studies revealed the importance of lipophilicity, electronic, and steric properties of the substituents in determining inhibitory potency (210, 211). 10.5. Coumarins. Functionalization of the hydroxyl group in 7-hydroxycoumarin (100) also represents a effective strategy in the generation of reversible MAOIs (212) (Figure 3). Although 100 is inactive, the benzyloxy derivative 101 is a potent but nonselective MAOI. Isozyme selectivity in this series is governed by the nature of the O-substituent. Thus, incorporation of heterocyclic groups or appropriate substituents on the benzyl moiety in 100 or 101 affords the potent and highly selective MAO-B inhibitors 102 and 103. In contrast, introduction of a sulfonyl ester bridge instead of an ether linkage reverses isozyme selectivity, generating selective MAO-A inhibitors as shown with 104. On the basis of SAR analysis, it is obvious that the ether and the sulfonyl linkages in these compounds are important for binding at the active site of the respective isozymes, since steric

Invited Review



hindrance around this region generates inactive compounds as exemplified with 105. 10.6. Tricyclics. Previous studies have shown that tricyclic compounds such as xanthone (106) possess MAO-A-selective inhibitory properties (Figure 4) (213, 214). Further structural modifications afforded a series of phenoxathiin dioxides that retained MAO-A potency and selectivity observed with xanthones (215, 216). BW 137OU87 (107) is one of the most potent and selective MAO-A inhibitors known with an in vitro Ki ) 10 nM and an in vivo ED50 ) 8 mg/kg (217). The lack of significant blood pressure changes in rats administered tyramine following pretreatment with BW 137OU87 was one of the most attractive features of this class of compound (215). Significant improvements in potency and selectivity were noted upon replacement of the 2-ethyl group in BW 137OU87 (107) with a 3-acetamido moiety as exemplified with 108 (MAO-A, IC50 ) 0.014 µM; MAO-B, IC50 > 10 µM) (218). Likewise replacement of the ether linkage in the central ring can be replaced with a carbonyl group results in compound 109 that retains MAO-A potency and selectivity. Inhibition is only discernible with aromatic 6:5:6 (compound 110) or 6:6:6 tricyclic compounds (compounds 107 and 108) whereas angular 6:6:6 tricyclics such as 111 or tricyclics in which one outer ring is not aromatic (compound 112) are inactive (218). Dramatic losses in MAO-A selectivity were observed upon replacement of the 3-acetamido group in 108 with bioisosteres such as imidazoline, 1,2,4-oxadiazoles, 1,3,4-oxadiazoles or tetrazoles and the mode of inhibition changed from competitive to slow, tight binding (219). On the basis of its overall pharmacological profile, 109 was advanced into clinical trials as an antidepressant/anxiolytic agent. Hepatotoxic side-effects in man,

however, caused it to be withdrawn from further consideration (220, 221). 10.7. MAOIs in Cigarette Smoke. Recent positron emission tomography (PET) studies on the brains of smokers have demonstrated a dramatic decrease in the activities of MAO-A and MAO-B relative to nonsmokers or former smokers (222, 223). These studies support previous observations on the inhibition of MAO isozymes by extracts of cigarette smoke and saliva from smokers (224-226). It has also been suggested that, since pulmonary MAO is principally responsible for metabolizing plasma serotonin, its inhibition by cigarette smoke promotes cigarette-associated lung disease (225). Overall, these observations raise the possibility that tobacco may contain a substance or substances with antidepressant and/or neuroprotective properties. Antidepressant effects, by virtue of MAO-A inhibition, may contribute to the addiction liability of tobacco in patients suffering from depression and neuroprotective effects, by virtue of MAO-B inhibition, could be linked to the reported low risk that smokers have for developing Parkinson’s disease (227-230). That MAO-A inhibitors could serve as effective tools in smoking cessation is supported by the observation that the reversible MAO-A inhibitor moclobemide facilitates the cessation of smoking in heavy smokers (228). The neuroprotective effects of smoking are exemplified by the observation that cigarette smoke attenuates MPTP-induced neurotoxicity in rodents (226, 231). Detailed studies on the MAO inhibitory properties of tobacco leaf extracts recently led to the characterization of the naphthoquinone 113 (Figure 3), a menadione analogue which displays reversible and competitive MAO inhibition [Ki(MAO-A) ) 3 µM; Ki(MAO-B) ) 6 µM] (232).

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This compound also is neuroprotective in the MPTP mouse model of neurodegeneration (233). 10.8. MPTP and Its Metabolites. Singer et al. reported that MPTP and its metabolites MPDP+ and MPP+ are reversible and selective MAO-A inhibitors (234) (Figure 3). The order of MAO-A inhibition is MPDP+ > MPP+ > MPTP. SAR studies on MPP+ analogues revealed that alkyl, alkoxy or halogen groups on the 2- or 3- or 4-positions on the C-4 phenyl ring of MPP+ were more potent and selective MAO-A inhibitors than MPP+ itself (235). That charged compounds such as MPDP+ and MPP+ are potent and selective MAO-A inhibitors indicates that MAO-A, but not MAO-B, may contain negatively charged residues for ion-pairing to the positively charged nitrogen in these compounds. 10.9. Indoles. The indole template appears in a variety of endogenous and exogenous MAOIs. R-Methylation of 5-HT, an indole-containing endogenous MAO-A substrate results in reversible MAOIs as discussed earlier. Many naturally occurring MAOIs, including β-carbolines (compound 114), isatin (115), and indoleamine-derived harmala alkaloids (compounds 116 and 117) also are MAO-A selective inhibitors (236-240) (Figure 4). Several synthetic indole analogues also are known to exhibit selective MAO-A inhibition with Ki values in the low micromolar range and MAO-A selectivity ratios ranging from 50 to 1000. Noteworthy examples include spirocyclopentylindoles such as 118, iminotetrahydrocyclopentylindole derivatives, exemplified with 119, and pirindole (120) (241-243). 10.10. Isoquinolines. Isoquinolines can be envisioned as cyclized versions of the endogenous MAO-B substrate PEA. Several substituted isoquinolines including 1-methyl-1,2-dihydro- and 1-methyl-1,2,3,4-tetrahydroisoquinolines as well as 1-methylisoquinolium ions (compounds 121-124) exhibit selective MAO-A inhibition in a reversible and slow, tight-binding fashion (244-246) (Figure 4). Although dihydro- and tetrahydroisoquinoline analogues (compounds 122 and 123) contain oxidizable amine functionalities, they are inactive as MAO substrates (244). 10.11. Moclobemide and Related Analogues. Moclobemide [Aurorix (125)] represents an example of a reversible, selective MAO-A inhibitor and is approved clinically as an antidepressant drug with a wide safety margin (Figure 5) (247). The mechanism of selective MAO-A inhibition by moclobemide is typical of that observed with other slow, tight-binding MAO inhibitors and reversibility of inhibition has been demonstrated in vitro as well as in vivo (248-250). Interestingly, the primary amine metabolite 126 derived from 125 exhibited time-dependent but reversible MAO-B selective inhibition (251). SAR analysis revealed that isozyme potency and selectivity were dependent on the integrity of the aminoethyl side chain and the nature of aromatic substituents. For example, replacement of the phenyl ring in 126 with a pyridinyl ring gave lazabemide [Ro 6327 (5)], a compound displaying superior MAO-B potency and selectivity (248, 252). In contrast, bulkier aromatic substituents reversed isozyme selectivity from MAO-B- to MAO-A selective inhibition as shown with Ro 41-1049 (127) (248, 252). Similarly, replacement of the benzamidyl moiety in 126 with bulky aryloxo or arylamino groups generates selective MAO-A inhibitors such as 128 and 129 (253, 254). In contrast, incorporation of smaller aryloxo substituents affords compounds such as

130 that display selective MAO-B inhibitory properties comparable to 126 (255). In some recent studies, MAO-B potency and selectivity of 126 have been dramatically improved by replacement of the amidyl moiety with the corresponding ester or carbamate bioisosteres as shown with 131 and 132, respectively (256, 257). 10.12. Miscellaneous. In addition to the various classes of reversible MAOIs discussed above, several structurally distinct series of heterocyclic MAOIs have surfaced in the primary and the patent literature (see Figure 5). They illustrate the structural diversity of reversible and selective inhibition of the MAO isozymes. Brofaromine [CGP 11305 (133)] is a selective, slow, tightbinding MAO-A inhibitor (258, 259). Available preclinical and clinical data indicate that brofaromine is effective and well tolerated in patients suffering from major depression and anxiety disorders (260, 261). RS-2232 (134) and its hydroxylated metabolite RS-8359 (135) also display reversible and selective MAO-A inhibition and are active as antidepressants in animal models (262, 263). Recent examples of potent, reversible and highly selective MAO-B inhibitors include the imidazolyl derivative 136 (MAO-B, IC50 ) 30 nM; MAO-A, IC50 > 20 000 nM) (264). Oral administration of 136 produced a dose-dependent inhibition of MAO-B activity in mouse brain with an ED50 value comparable to that observed with the MAO-B irreversible inactivator (R)-deprenyl. In some recent studies, Castagnoli et al., disclosed that 7-nitroindazole (137, 7-NI), previously described as a neuronal nitric oxide synthase inhibitor, also inhibited MAO-B in a reversible, competitive fashion with a Ki value of 40 µM against the purified isozyme (265).

11. Irreversible MAOIs A general strategy that allows for the design of selective, irreversible MAOIs involves the incorporation of substituents on the nitrogen atom of isozyme selective substrates which undergo MAO-catalyzed conversion to electrophilic intermediates that alkylate the active site of the enzyme. N-Substituents that are capable of imparting irreversible inhibition properties to MAO substrates include amino (hydrazines), allyl, propargyl, cyclopropyl, cyclobutyl, trialkylsilanyl, oxazolidinonyl, and furanoyl groups. For example, the MAO-B-selective substrate benzylamine is converted to the MAO-Bselective and irreversible inhibitor pargyline (4) by incorporating a propargyl group on the nitrogen atom that is susceptible to enzyme-mediated oxidation (266268). Furthermore, extending the distance between this electron rich center and the aromatic ring or incorporating a bulky group on the aromatic ring of irreversible MAO-B selective inhibitors affords irreversible MAO-A selective inhibitors. This is apparent from structural differences between (R)-deprenyl (3) (MAO-B selective) and clorgyline (4) (MAO-A selective) (see Chart 1). The mechanism of MAO inactivation by hydrazine derivatives (269, 270) such as phenylhydrazine (138) (Figure 6) is thought to involve an initial MAO-catalyzed dehydrogenation to a corresponding phenyldiazine 139 intermediate which in turn loses a H atom and N2 to afford the phenyl radical 140. On the basis of results obtained from model studies, covalent attachment of 140 has been proposed to occur at the 4a-position on the flavin group in MAO-B (271). Allyl- and propargylamines undergo MAO-catalyzed oxidation to the corresponding

Invited Review


Figure 6. Proposed mechanism of covalent inactivation of MAO by irreversible inhibitor classes.

dieniminium and eyniminium species, 141 and 142, respectively. These highly electrophilic Michael acceptors then inactivate the enzyme by bonding covalently to an active site residue or the flavin group (272-276). Unlike hydrazines, covalent bond formation with allyl- or propargylamines does not occur on the 4a-position in the flavin moiety. Comparison of the spectral properties of the inactivated enzyme to those observed in model studies on the photoreduction of synthetic flavins with propargylamines suggest the N-5-position on the flavin as the site of covalent modification (275-277). The pathway(s) responsible for the mechanism-based inhibition by cyclopropylamines remains the subject of intense debate (278-284). One of the most widely accepted proposals involves the initial single electron transfer from cyclopropylamines such as N-cyclopropylR-methylbenzylamine (143) to the flavin cofactor to generate the aminium radical cation 144. Spontaneous

ring opening of the cyclopropyl group in 144 generates the primary carbon-centered 145 that alkylates an active site residue leading to covalent inactivation. Peptidemapping studies followed by mass spectral analysis revealed that 143 labels Cys365 in bovine liver MAO-B, which corresponds to Cys374 and Cys365 in human MAO-A and MAO-B, respectively (49). Not all cyclopropylamines, however, are mechanism-based inactivators of MAO. Certain MPTP analogues bearing N-cyclopropyl substituents have been reported to be excellent MAO-B substrates that do not inactivate MAO (88-90). These compounds undergo R-carbon oxidation to the corresponding dihydropyridinium species, the same pathway observed with MPTP. As noted earlier, irreversible inhibition by aryl oxazolidinones such as MD 780236 (87) is dependent on the presence of the aminomethyl group, since replacement of nitrogen with other heteroatoms alters the mode of

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Figure 7. SAR studies on propargylamines as irreversible MAO inhibitors.

inhibition from irreversible to reversible. The proposed mechanism of inhibition involves initial R-carbon oxidation of the aminomethyl group to give the iminium species 146 that covalently modifies MAO by reacting with an active site residue to generate adduct 147 (285, 286). Generally, enzyme-inhibitor adducts such as 147 are thought to undergo spontaneous decomposition to the corresponding iminium species and active enzyme via β-elimination. Silverman and co-workers attribute the enhanced stability of 147 to the stabilizing effect of the sp3 carbon to which the enzyme is attached by the electron-withdrawing ability of the heteroatoms in the oxazolidinone ring (N, O, and the CdO groups) (287, 288). Support for this proposal is provided by the observation that furanones and pyrrolidinones such as 148 and 149, respectively, irreversibly inhibit MAO (287, 288). Additional examples of irreversible MAOIs that demonstrate such behavior include MPTP and milacemide. Oxidation of MPTP, particularly by MAO-A, is accompanied by irreversible inactivation (289, 290). The most likely pathway involves the alkylation of an active site residue by MPDP+ to form 150, the stability of which may be controlled by the presence of the electronwithdrawing styryl framework. A second example is provided with the anticonvulsant drug milacemide (41) which undergoes selective MAO-B-catalyzed oxidation to the iminium species 151 that is thought to alkylate the protein yielding 152 (115). The acetamido group in milacemide is most likely the functionality that stabilizes the enzyme-inhibitor adduct 152. Apart from mechanistic studies, elaborate SAR studies also have been conducted with propargylamines in an attempt to optimize their irreversible inhibitory properties (Figure 7). Studies with a series of 5-hydroxyindolyl2-alkylamines indicate that optimal MAO-A potency and selectivity is found with 5-hydroxyindolyl-2-methyl-Nmethyl-N-propargylamines such as 153 (291). Replacement of the N-methyl group with higher alkyl or aromatic groups or extension of the 2-methylamino side chain results in significant reduction in inhibitory efficiency (292, 293). Incorporation of lipophilic substituents on the 5-hydroxy group reverses isozyme selectivity. For example, O-benzylation of 153 generates 154, an MAO-B selective inhibitor (294, 295). R-Methylation of the propargyl moiety in these compounds changes their mode of inhibition from irreversible to reversible. Thus, enantiomers 155a and 155b obtained following R-methylation of clorgyline demonstrate competitive and reversible inhibition (296). An interesting outcome concerning the

targeting of propargylamines as isozyme selective inhibitors was noted with (R)-deprenyl (297). Quaternization of the nitrogen in this selective MAO-B inhibitor and related analogues resulted in compounds such as 156 that demonstrated selective MAO-A inhibition. Such a complete inversion of selectivity is probably due to a specific interaction of these positively charged amines at a hydrophilic region available in MAO-A but not MAOB. Analysis of the primary amino acid sequence suggests that the negatively charged Glu286 and Glu290 in MAO-A are the most probable candidates for ion-pairing with the positively charged amines. In MAO-B, this ionpairing may not be possible since Phe and Met replace Glu at positions 286 and 290, respectively. Site-directed mutagenesis on these residues may help in resolving these issues. Besides aromatic compounds, simple aliphatic propargylamines such as 157 also irreversibly inhibit MAO-B (298-300). As observed with aromatic compounds, replacement of the methyl group on the nitrogen atom with hydrogen or other higher alkyl groups leads to inactive compounds and optimal potency and selectivity are discernible with propargyl and 2-but-1-ynyl groups. Four to seven carbon branched chain compounds are as potent as or more potent than (R)-deprenyl as MAO inhibitors. Substituting the terminal carbon with polar functionalities such as hydroxyl or carboxylate groups generates inactive compounds. Results of SAR and biochemical studies show that aliphatic propargylamines such as 157 function as neuroprotectants against toxin-induced norepinephrine depletion in mice and rats (301, 302).

12. Concluding Remarks In conclusion, an attempt has been made to summarize the interactions of nitrogen-containing xenobiotics with MAO with emphasis on potential relationships between metabolism and pharmacological activity. The discovery of the two forms of MAO has led to significant advances in our understanding of the physiological and biochemical roles that these enzymes play in normal biological processes and in disease states. Particularly exciting are the findings that the life-threatening hypertensive crises associated with some irreversible MAOIs can be avoided with reversible inhibitors. The development of reversible and isozyme selective MAOIs offers renewed hope for generating superior antidepressants and anti-parkinsonian agents by virtue of the selective inhibition of MAO-A and MAO-B, respectively. Apart from their pharmacological utility, isozyme selective MAOIs are also useful as tools to probe active site differences between the two isozymes and to construct models of the active site. Since MAO is an integral membrane protein, it is difficult to crystallize and its three-dimensional structure has not been reported. Site-directed mutagenesis studies and SAR analysis on MAO substrates and inhibitors are presently the only available tools to assess the threedimensional features of these active sites. For instance, recent studies by Geha et al. have shown that mutation of the nonconserved isoleucine and tyrosine residues at position 335 and 326 in MAO-A and MAO-B, respectively, to the corresponding tyrosine and isoleucine residues results in mutated proteins that exhibit reversed selectivity toward substrates and inhibitors (65). Thus, the mutant MAO-B Tyr326Ile displays increased activity with the MAO-A selective substrate 5-HT and increased

Invited Review


sensitivity to inhibition by the MAO-A selective mechanism-based inhibitor clorgyline. The recent availability of high-level MAO expression systems should encourage additional studies along these lines that were not previously possible (93). The past decade also has witnessed a resurgence of interest in MAO, particularly due to its involvement in the metabolism of xenobiotics. The most dramatic illustration is the MAO-B-catalyzed bioactivation sequence leading to the formation of the pyridinium mitochondrial neurotoxin MPP+ from the tetrahydropyridine proneurotoxin MPTP. The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events that, fortunately, are unlikely to be encountered with many substances. In addition to such bioactivation processes, the MAOs also catalyze the metabolism of a variety of drugs. A dramatic illustration is the role of MAO-A as the principal phase I enzyme involved in the clearance of the antimigraine drug Sumatriptan in humans. The MAO-A substrate properties of Sumatriptan and the related drugs, zolmitriptan and rizatriptan, are not surprising, given their structural similarity to 5-HT, the preferred MAO-A substrate. It is worth pointing out that in the triptan series, only the acyclic 2° and 3° amines (sumatriptan, N-desmethylzolmitriptan, and rizatriptan) are MAO substrates; the cyclic 3° amines (eletriptan and naratriptan) are not substrates. The lack of MAO substrate properties of eletriptan and rizatriptan may be due to the absence of an allylic double bond found in the 1-methylpyrroldinyl- and the 1-methylpiperidinyl derivatives, which are excellent MAO substrates. Overall, a better understanding of the tissue distribution of the MAOs may help to address questions of the possible roles of MAO in first pass metabolism and the exposure to amine xenobiotics, especially those that are inhaled or administered orally. Furthermore, the finding that several amine-containing drugs including the triptans, primaquine, haloperidol, milacemide, and diltiazem are MAO substrates raises the possibility of potentially important drug-drug interactions that may lead to sideeffects in patients on MAOIs as has been demonstrated with citalopram. Given the structural diversity of MAO substrates, any small molecule drug containing a RCH2NR1R2 functionality may be metabolized by MAOs. Likewise, given the structural diversity of MAOIs, any small molecule xenobiotic bearing resemblance to known or hitherto unknown structural class may function as a MAOI as observed with the anti-bacterial agent linezolid. Thus, inhibition and modulation of MAOs can result in undesirable elevations in plasma concentrations of MAO substrates and in some instances cytochrome P450 substrates.

Acknowledgment. The studies cited in this review originating in Prof. Castagnoli’s laboratory were supported by the National Institute of Neurological and Communicative Disorders and Stroke (NS 28792) and by the Harvey W. Peters Center for the study of Parkinson’s Disease.

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