The Mechanism of Action of the 2-Phenylcyclopropylamine Type of Monoamine Oxidase Inhibitors

Abstract

In continuation of our studies of the mechanism of action of monoamine oxidase (MAO) using deuterium isotope effects as a tool,2-5 we have examined the effect of deuterium substitution on the carbons alpha and beta to the amine function of the substrate kynuramine (I and II) on the kinetics of oxidation by rat liver MAO. The a-bisdeuteriokynuramine (I) was prepared by lithium aluminum deuteride reduction of indoleacetonitrile,6 then ozonolysis according to the procedure of Weissbach et al.1 The 3-bisdeuteriokynuramine (II) was obtained by prolonged treatment of kynuramine dihydrobromide with excess deuterium oxide at 100°. Both substrates were labeled to the extent of at least 90% as determined by n.m.r. analysis. The MAO was prepared according to Hawkins8 and the rates of oxidation measured spectrophotometrically folloiving the procedure of Weissbach et aV The results are shown in Fig. 1, where it can be seen that the ratio of the slopes of the initial velocities / . is 2.1 when (I) is compared with kynuramine. The magnitude of this primary(1) This investigation represents a portion of the thesis submitted by J. M. in partial fulfillment of the requirements for the M.Sc. degree in Biochemistry.(2) B.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…From various studies based on crystallography, it was concluded that an almost common structural feature of substrate and inhibitors usually is an amino or imino group, which seems to play an essential role in the orientation and complex formation at the active site of the enzyme . In spite of the considerable progresses in the understanding of interactions of MAO isoforms with their specific substrates or inhibitors, there are not any available rules for the rational design of new, potent, and selective MAOIs.…”

“…From various studies based on crystallography, it was concluded that an almost common structural feature of substrate and inhibitors usually is an amino or imino group, which seems to play an essential role in the orientation and complex formation at the active site of the enzyme. 132 Figure 11). [137][138][139] Although MAOIs have been extensively used in the clinic, the use of nonselective and selective MAO-AIs declined after the realization that these drugs potentiate the sympathomimetic effects of the dietary amine, tyramine.…”

“…Amr et al 199 synthesized a series of chiral linear and macrocyclic pyridines (126)(127)(128)(129)(130)(131)(132)(133) and screened them for MAO-B inhibition activity using rat brain synaptosome ( Figure 55). All the compounds showed potent inhibitory activity against MAO-B and were found to be more potent than selegiline.…”

Synthesis and molecular modeling of some novel hexahydroindazole derivatives as potent monoamine oxidase inhibitors

“…[12][13][14][15][16][17] It was reported that numerous compounds among the great variety of substituted hydrazines behave as MAO inhibitors [18][19][20] and a common structural feature of substrates and inhibitors is an amino or imino group playing in interaction at the active site of the enzyme. 21 2-Pyrazolines can also be considered as a cyclic hydrazine moiety. For this reason, researchers have investigated MAO and other amine oxidase inhibition activities of 2-pyrazolines and found high activity (Fig.…”

Synthesis of Azetidines

“…It has been postulated that the potent monoamine oxidase (MAO) inhibitory activity exhibited by 2phenylcyclopropylamine might be explained in terms of the electronic and steric properties of the cyclopropane ring system (1,2). Larger cycloalkyl analogs including 2-phenylcyclobutylamine are much less active M A 0 inhibitors, presumably for steric reasons and because of a change of electronic properties of the ring system.…”