Potent MAO-A inhibitor

Basically, the catalytic site of MAOs is thought to consist of two distinct parts, namely a polar-binding site for the amino group and a hydrophobic entrance cavity [64]. Several 2-aminoethylcarboxamides are potent MAO inhibitors. The monocyclic compounds Ro 19-6327 (14a) and Ro 19-6491 (14b) have been shown to be highly selective for MAO B and the fluorinated dicyclic Ro 41-1049 (15) is a potent MAO A inhibitor, while Ro 41-0770 (16) was found to be quite nonselective [65]. 

On the other hand the ( )-isomer of deprenyl is a much more potent MAO-B inhibitor than the (+)-isomer. For these reasons racemic deprenyl has been replaced by ( )-deprenyl in clinical practice. In the racemic local anesthetic prilocaine (Figure 26.6) only the R-( )-isomer is metabolized to an aniline derivative (ortho-tolnidine) and to the corresponding para- and ortho-aminophenols that are highly toxic and responsible for met hemoglobinemia. ... 

Deeper structural studies by crystallography, molecular modeling, and SAR were performed until recently to modulate the potency and the selectivity of synthetic harmine (1) derivatives (see e.g., [37]). These smdies showed that lipophilic substituents, replacing the methyl group of the methoxy moiety at C-7, increased the potency for MAO-A inhibition in comparison with 1. Additionally, it was found that synthetic compounds containing a cyclohexyl group as substituent at C-7 were more potent MAO-B inhibitors than 1. Docking simulations demonstrated that this cyclohexyl chain points to a lipophihc pocket in the entrance cavity of the human MAO-B active site. 

Monoamine oxidase (MAO) inactivates serotonergic and catecholaimnergic neurotransmitters MAO (A and B) inhibitors exhibit mood elevatmg properties 5-Fluoro-Ot-methyltryptamine 19) is an important MAO A-seleUive inhibitor In the treatment of certam depressive illnesses, 4-fluorotranylcypromine (20b) is 10 tunes more potent than the parent tranylcypromme (TCP, 20a) The enhanced m vivo activity may be due to increased lipophihcity at20b and/or to blockade of metabohc para hydroxylation [52]... 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

LSD1. A recent study identified LSD2 inhibitors that exhibited a 10-55-fold selectivity for LSD2 over LSD1, but that also potently inhibited MAO A and MAO B [109]. As specific inhibitors for individual demethylases and their isoforms are identified, it will be possible to elucidate the role that each enzyme plays in the epigenetic control of gene expression. 

Antidepressants of this class, such as moclobemide, have a high selectivity and affinity for MAO-A. Flowever, unlike the MAOIs, the RIMAs are reversible inhibitors of the enzyme and can easily be displaced from the enzyme surface by any primary amine which may be present in the diet. This means that the dietary amines are metabolized by MAO in the wall of the gastrointestinal tract while the enzyme in the brain and elsewhere remains inhibited. Thus the RIMAs have brought the MAOIs back into use as antidepressants in general practice. It is now evident that the RIMAs are not as potent as most currently available antidepressants. 

In Section 1.1.1, L-deprenyl (2) was discussed as a potent selective MAO B inhibitor. Its p-fluoro analogue, fludeprenyl (7), was shown to retain the irreversible and selective inhibitory effects of its parent compound, with similar potency in vitro in rat tissue and in vivo in mice [33]. Both compounds have also been reported to have similar protective actions against transient global cerebral ischemia in gerbils. With L-deprenyl (2), these effects occurred at doses below those which inhibit MAO B, while the effects of the p-fluoro analogue 7 occurred only at doses that also inhibit MAO B activity [33b,34]. 

Tranylcypromine ( rans-2-phenylcyclopropylamine, TCP, 8a) has close structural similarity to amphetamine (2-amino-1-phenylpropane) and is known as a nonhydrazine, nonselective, and irreversible inhibitor of both MAO A and B. It is also a potent reversible inhibitor of CAOs [36,37], Tranylcypromine has an important clinical use for treatment of certain depressive illnesses, particularly of nonendo-genous and atypical depressions and depressions associated with anxiety, agitation, phobias, and anergia [38-40], In combination with lithium, it is also applied for treatment of refractory depression [41], Recent reports also discussed MAO inhibitors as useful agents against neurodegenerative disorders such as Parkinson s or Alzheimer s diseases [42], Despite impressive clinical successes, clinical use of tranylcypromine and other MAO inhibitors is limited by various problems, including the cheese effect discussed in Section 1,... 

Haloallyl amines also have been studied as inhibitors of SSAO. The 2-aryl-3-haloallylamines proved to be potent irreversible inhibitors of rat aorta SSAO. Hydrophobic substituents on the aryl ring enhanced activity, while phenolic groups decreased activity [78]. The MAO B selective ( )-2-(3, 4 -dimethoxyphe-nyl)-3-fluoroallylamine (22d) inhibited rat SSAO in vascular and brown adipose tissues and was selective relative to inhibition of MAO A [79]. MDL 72974A (25) is a potent irreversible inhibitor of both MAO B and SSAO with a 190-fold lower affinity for MAO A [80]. 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

Fuller reported that A/-phenacyl-cyclopropylamine hydrochloride (48) displayed a slight preference for MAO B inhibition, and that analogues with various substituents on the phenyl ring were inhibitors of MAO A [117]. Subsequent research revealed that A/-[2-(o-chlorophenoxy)-ethyl]-cyclopropylamine (Lilly 51641) (42) had selectivity toward MAO A [118]. The iodo analogue of compound 42, A/-[2-(o-iodophenoxy)-ethyl]-cyclopropylamine (LY121768) (49), also proved to be a MAO A-selective irreversible inhibitor [119]. Silverman and coworkers reported that 1-phenylcyclopropylamine (50) and A/-cyclopropyl-a-methylbenzyla-mine (51) are 50 times more potent irreversible inhibitors for MAO B than MAO A, while 1-benzylcyclopropylamine (52) showed some selectivity for MAO A [120]. A/-Cyclopropyl-indolylmethylamine (53), A/-cyclopropylbenzylamine (54), and A/-(1-methylcyclopropyl)benzylamine (55) were also shown to be good inhibitors, but the selectivities were not reported [121]. 

Interestingly, fluorination at the 2-position of 1-phenylcyclopropylamine (50), which is known as a selective inhibitor of MAO B relative to MAO A, reversed the selectivity and resulted in a potent inhibitor selective for MAO A [133,134] (Table 5). p-Substituted analogues of 1-phenylcycloropylamine (62b-e, 63b-e) are also MAO A-selective inhibitors and showed the same level of inhibitory potency as 62a and 63a. 

Protection was not associated with MAO-B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of selegiline. Protection was not associated with inhibition of dopamine uptake by selegiline because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. Antioxidant ascorbic acid (200 iM) also protected BSO-induced cell death, suggesting that oxidative events were involved. This... 

Substituted benzylsilylmethylamines have been synthetized88,489,490 and tested on rat brain MAO as potent and selective (MAO-B versus MAO-A) enzyme activated irreversible inhibitors of rat brain MAO-B in vitro.490 491... 

Deprenyl (Selegiline), developed in the early 1960s as a new spectrum psychostimulant and potent MAO inhibitor, later proved to be, as the first selective inhibitor of MAO-B, indispensable for investigating the nature and function of B-type MAO. Hundreds of clinical studies with the drug were designed thereafter in the firm belief that selective blockade of MAO-B was responsible... 

Since (-)-deprenyl is a highly potent and selective inhibitor of MAO-B, we performed a structure-activity relationship study to develop a deprenyl-derived enhancer substance that is free of the MAO-B inhibitory property (Knoll etal. 1992a). (-)-l-Phenyl-2-propylaminopentane [(-)-PPAP] has been chosen as our reference substance with this pharmacological profile. 

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