Inhibition cyclopropylamines

In the late 1960s, different types of cyclopropylamines, the A/-substituted cyclopropylamines, were reported [111]. One of the most interesting compounds in the new class was A/-[2-o-chlorophenoxy]-ethyl]-cyclopropylamine (Lilly 51641) (42). This compound noncompetitively inhibited the MAO-catalyzed oxidation of serotonin, tyramine, phenylethylamine, and tryptamine in vitro and increased the serotonin concentration in the whole rat brain in vitro. In structure-activity studies on a series of m- and p-aromatic substituted A/-(phenoxyethyl)cyclopropylamines (43), the degree of inhibition correlated well with a and % values [112]. 

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]. 

On the other hand, a recent crystallographic study revealed that the trans-2-phenylcyclopropylamine (8a) forms a cyclopropyl ring-opened adduct with MAO B at the flavin C(4a), and no evidence was obtained for inhibitor binding at Cys-365 [70,127]. From this observation, Edmondson and coworkers suggested [70] that the inhibition mechanism might be accommodated by a mechanism similar to that proposed by Sayre et al. for the quinone-mediated oxidative cleavage of cyclopropylamines [128]. 

Fig. 3. Proposed inhibition mechanisms by cyclopropylamines. (a) From Ref. [126e] (b) from Ref. [125a] (c) from Ref. [126a] (d) from Ref. [70].

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

In contrast to the substantial work with MAO, relatively little research has been reported on the mechanism of inhibition of copper-containing amine oxidases and SSAO by cyclopropylamines. Bovine plasma amine oxidase, equine plasma amine oxidase, Escherichia coii amine oxidase, and Arthrobacter globiformis amine oxidase were inhibited by frans-2-phenylcyclopropylamine (8a) and the mode of inhibition was shown by spectral and crystal structure analyses to be competitive and reversible [36,37,129],... 

As discussed above, many cyclopropylamines are good inhibitors of MAOs. In addition, as discussed in Section 3.2, fluorine substitution had substantial effects on the inhibition of MAOs by such analogues as allylamines. We undertook a broadly based study of the effects of fluorine substituted on the cyclopropyl ring of cyclopropyl amines on potency and selectivity of amine oxidase inhibition. In addition to effects on amine pKg and lipophilicity, we expected additional consequences resulting from altered geometry and ring strain due to the presence of fluorine. 

We have examined the above-described series of trans- and c/s-2-fluoro-2-phenylcyclopropylamine analogues (60a-d, 61a-d) as inhibitors of recombinant human liver MAO A and B [134]. The presence of fluorine attached to a cyclopropane ring, especially for frans-isomer 8a, was found to result in an increase in inhibitory activity toward both MAO A and B (Table 4). In addition, p-substitution of electron-withdrawing groups, such as Cl and F, in the aromatic ring of the frans-isomers (60b-d) increased the inhibition of both enzymes. On the other hand, the introduction of fluorine at 2-position of c/s-isomer 8b resulted in loss of inhibitory activity for both MAO A and B, and no further p-aromatic substitution for c/s-isomer greatly affected on the inhibitory activity with either enzymes. In addition, both MAO A and B were selectively inhibited by the (1S,2S)-enantiomer of 60a, while no inhibition was observed with the (1f ,2f )-enantiomer [134]. As already described in the former section, several questions on the mechanistic pathway for MAO inhibition by cyclopropylamines still remain. However,... 

R.W. Fuller, M.M. Marsh, J. Mills, Inhibition of monoamine oxidase by A/-(phenox-yethyl)cyclopropylamines. Correlation of inhibition with Hammett constants and partition coefficients, J. Med. Chem. 11 (1968) 397-398. 

S. Ye, S. Yoshida, R. Frohlich, G. Haufe, K.L. Kirk, Fiuorinated phenyicyciopropyiamines. Part 4. Effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by 1-aryl-2-fluoro-cyclopropylamines, Bioorg. Med. Chem. 13 (2005) 2489-2499. 

The most commonly used MAO inhibitors include hydrazines, such as iproniazid, Marsilid, Marplan, Niamid, Nardil, Catron also nonhydrazines such as propargylamines, cyclopropylamines, aminopyrazine derivatives, indolealkylamines, and carbolines. MAO-inhibiting materials discussed in this book include yohimbine various tryptamines, especially 5-MeO-DMT and the alpha-methyltryptamines and the various harmala alkaloids. The latter are especially potent inhibitors, but, like yohimibine and the tryptamines, are short-lasting in action (30 minutes to several hours). Some of the commercial MAO inhibitors listed above are effective for several days to several weeks. 

For some years the mitochondrial flavoenzyme monoamine oxidase (MAO) was the target of selective inhibition in the development of tranquillizing drugs " One potent inhibitory class was that of cyclopropylamines of which tranylcypramine (164) (trans-2-phenylcyclopropylamine) was a successful, albeit clinically dangerous and eventually unusable agent °. Tranylcypramine (164) and analogous cyclopropylamines turn out to... 

Substituted cyclopropylamines as 1-benzylcyclopropylamine (635d), inhibited MAO less strongly in vivo it was found that this type of cyclopropylamines showed preferentially anorectic activity L... 

Fuller, Marsh, and Mills (22) applied the Hansch approach to a series of 16 N-(phenoxyethyl)cyclopropylamines which are monoamine oxidase (MAO) inhibitors. The activity is expressed as p/50, the negative logarithm of the concentration of the derivative which inhibits MAO 50%. They used a dummy variable, y, to designate the steric effects of meta substitution. Their results are summarized in Figure 24. 

Figure 24. Inhibition on monoamine oxidase by N-(phenoxyethyl)cyclopropylamines (22)...

Macdonald TL, Zirvi K, Burka LT, Peyman P, Guengerich EP (1982) Mechanism of cytochrome P-450 inhibition by cyclopropylamines. J Am Chem Soc 104 2050-2052... 

Newer Semi-Empirical Approaches - Fuller, Marsh and Mills have derived eq 21 which correlates inhibition of monoamine oxidase by N-(Phenoxy-ethyl)-cyclopropylamines. In eq 21, y is an arbitrarily defined steric constant. Equation 21 was used to predict the activity of two new de-... 

---