1-phenylcyclopropylamine

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]. 

Silverman and coworkers have carried out extensive research on the mechanism of inactivation of MAO by cyclopropylamine analogues. They first reported in the early 1980s that A/-cyclopropyl-A/-arylalkylamines are mechanism-based inactivators of MAO [121,125], The mechanism proposed was enzyme-catalyzed one electron oxidation of A/-cyclopropylamines to give reactive ring-opened products which further react with either flavin and/or a cysteine residue, depending on the structure of the inactivator. According to their reports [120,125, 126], 1-phenylcyclopropylamine (50) attached reversibly to a cysteine residue and irreversibly to the flavin when it activated MAO B, whereas 50 modified only the flavin during inactivation of MAO A. In the case of frans-2-phenylcyclopropy-lamine (8a) and A/-cyclopropyl-a-methylbenzylamine (51), both MAO A and B are inactivated by attachment to a cysteine residue (Fig. 3). 

Inhibition of copper-containing tyramine oxidase by fluorinated 1-phenylcyclopropylamines (62a-e, 63a-e, 64) also was investigated. These compounds displayed relatively poor activity as inhibitors [130, 133] (Table 3). 

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. 

Table 5. IC50 values and inhibition type of 2-fluoro-1-phenylcyclopropylamines for recombinant human liver MAO A and [133]. Adapted by permission of Elsevier Ltd. Copyright 2005.

Using similar systems Silverman and coworkers have explored the oxidation of a variety of cyclopropyl amine substrates by MAO [16, 17, 196, 197]. Involvement of electron transfer in such processes would lead to the formation of the ring-opened alkyl radical and subsequent attachment of the resultant alkyl radical to the enzyme would result in its inactivation. Scheme 17 shows the proposed mechanism for enzyme deactivation by 1-phenylcyclopropylamine. 

In contrast to the formation of covalent adducts at flavin or at an amino acid residue by A -cyclopropyl-Af-arylalkylamines and 2-phenylcyclopropylamine, respectively, inactivation of MAO by 1-phenylcyclopropylamine leads to both types of adducts 100). Both inactivation pathways are proposed to originate from an initial one-electron oxidation by flavin to produce a common intermediate, the amine radical cation 33 in Scheme 22 (compounds 33-39). Homolytic cyclopropyl ring opening would lead to the reactive primary alkyl radical 34, which could be captured by the active site radical, either flavin semiquinone or amino acid centered. Subsequent hydrolysis of the imine, pathway (a), forms a... 

Treatment of the reduced adduct with pronase and subsequent reduction with Raney nickel led to the release and isolation of trans-/3-methylstrene 39. Raney nickel is known to cleave carbon-sulfur bonds specifically (777). Furthermore, the expected product from cleavage of the carbon-sulfur bond of the reduced adduct is 1-phenyl-1-propanol however, under the conditions of the Raney nickel reduction, 1-phenyl-1-propanol is dehydrated to trans-/3-methylstyrene (770). This result suggests that the amino acid residue is cysteine. The finding that the total number of cysteine residues detected with 5,5 -dithiobis(2-nitro-benzoic acid) decreases by one in the denatured, 1-phenylcyclopropylamine-... 

Silverman and Zieske have rationalized how a protein nucleophile other than flavin is involved in MAO inactivation reactions, and why different inactivator compounds specifically react with flavin, protein amino acids, or both (100). Hydrogen atom donation from a cysteine residue to the flavin semiquinone radical would produce a thiyl radical, which could then capture the primary or secondary alkyl radical generated on cyclopropyl ring opening from the amine radical cation of the inactivator. The hydrogen atom abstraction reaction between the flavin and active site amino acid may be an equilibrium process such that either species could be present at any turnover. Hence, a combination of steric constraints and proximity to either the flavin semiquinone radical or the thiol radical will determine the site of adduct formation for a particular inactivator structure. A two-dimensional representation is shown in Scheme 23 (compounds 40-42), which illustrates the proposed equilibrium between the flavin semiquinone radical and amino acid as well as the proposed intermediates for the inactivation of MAO by A-(l-methylcyclopropyl)benzylamine 40 (104), rrradical center relative to the particular protein radical is consistent with proposed site of attachment of inactivator to protein 40 is near the flavin radical, such that exclusive flavin attachment occurs, 41 is positioned closer to the amino... 

Scheme 23. Proposed role of flavin semiquinone radical, amino acid residue, and possible intermediates in the inactivation of MAO by N-(I-methylcyclopropyl)benzylamine (40) (.104), trans-2-phenylcyclopropylamine (41) (i09), and 1-phenylcyclopropylamine (42) (JOO).

Seven-membered ring formation. Reaction of 3,5-di-7-butyl-l,2-benzoquinone with 1-phenylcyclopropylamine gives a mixture of the... 

Hiyama et al. [7] reported previously that 1-phenylcyclopropylamine is oxidized by NaOCl or lead tetraacetate to ethylene and benzonitrile via the intermediacy of the nitrenium ion ... 

Taavitsainen P, Juvonen R, Pelkonen O (2001) In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene. Drug Metab Dispos 29(3) 217-222... 

Tranylcypromine Tranylcypromine, ( )-lran5-2-phenylcyclopropylamine (7.2.10), differs from the drugs described above in that it is not a derivative of hydrazine. It is synthesized from the ethyl ester of 2-phenylcyclopropan carboxylic acid (7.2.7), which... 

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,... 

Cyclopropylamines have been the subject of extensive research over a long period for a variety of reasons. Included in the results of this research was the discovery that certain cyclopropylamines were inhibitors of flavin-containing MAO. Lacking a hydrazide moiety, these compounds were expected to be devoid of liver toxicity, rrans-2-phenylcyclopropylamine (tranylcypromine) (8a), discussed in Section 2.2, appears to be the first cyclopropylamine to be used in clinical trials [109]. Norepinephrine concentrations in the rat brain could be increased by oral administration of lower doses of 8a in comparison to iproniazid [110]. 

With the recognition in the late 1960s that there are two forms of MAO (Section 1.1.1), potential therapeutic implications related to isozyme selectivity needed to be considered in MAO inhibitor development. (The early literature also reveals some lack of distinction between copper-containing and flavin-containing MAOs.) An important case in point involves the clinical side effects associated with the cheese effect (Section 1.2.1) that made clear that there would be important clinical advantages to having available isozyme-selective inhibitors [115]. Follow-up studies with the well-known cyclopropylamine inhibitor trans-2-phenylcyclopropylamine (8a) demonstrated that this clinically useful compound is an irreversible inhibitor of MAO, but that it had no selectivity toward either MAO A or B [116]. 

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]. 

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],... 

TraA7s-2-phenylcyclopropylamine (8a) and its c/ s-isomer (8b) are competitive inhibitors of microbial copper-containing SSAO [37,130], Introduction of fluorine at position 2 of 8a and 8b had dramatic effects on the inhibition of microbial tyra-mine oxidase from Arthrobacter sp. by these compounds [130], Compound 60a with a cis arrangement of the fluorine substituent and the amino group was 10 times more potent an inhibitor than compound 8a. In contrast, the corresponding diastereomer 61a with a trans arrangement of the two substituents was five times less active than 8a (Table 3). 

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,... 

Reaction of rra s-Ar,A -dimethyl-2-phenylcyclopropylamine with di-methylamine in methanol to give the open-chain enamine 1-dimethylamino-3-phenyl-l-propene [178]. 

The bioactivity of the frans-2-phenylcyclopropylamine 10 (tranylcypromine) which is also a potent inhibitor of MAO and an efficient, albeit dangerous tranquillizing drug, would result of a net two-electron oxidation process leading to the cyclopropyliminium ion 11, which then undergoes nucleophilic substitution by a thiol group of cysteine yielding 12, Eq. (5) [14]. 

PHENYL CYCLOHEXYL KETONE see PES750 trans-2-PHENYLCYCLOPROPYLAMINE see PET750 PHENYLDIBROMOARSINE see DDR200 PHENYL DICHLORARSINE see DGB600 PHENYLDICHLOROARSINE see DGB600 PHENYLDICHLOROPHOSPHINE see DGE400... 

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... 

The most outstanding effect of rrans-2-phenylcyclopropylamine (5) (generic names tranylcypromine, transamine) is the inhibition of monoamine oxidase (MAO) ... 

For reviews see. (a) Welch, J. T. (1987) Tetrahedron report number 221 Advances in the preparation of biologically active organofluorine compounds. Tetrahedron, 43, 3123-3197. (b) Resnati, G. (1993) Synthesis of chiral and bioactive fluoroorganic compounds, Tetrahedron, 49, 9385-9445. (c) Soloshonok, V. A. (ed.) (1999) Enantiocontrolled Synthesis of Fluoroorganic Compounds Stereochemical Challenges and Biomedicinal Targets, John Wiley Sons, Ltd, Chichester, UK. (d) Rosen, T. C., Yoshida, S., Kirk, K. L. and Haufe, G. (2004) Fluorinated phenylcyclopropylamines as inhibitors of monoamine oxidases. ChemBioChem., 5, 1033-1043. 

Song, Y., Yoshida, S., Frohlich, R., et al. (2005) Fluorinated phenylcyclopropylamines. Part 4 Effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by... 

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