title: N-[2-(o-iodophenoxy)ethyl]cyclopropylamine hydrochloride (LY121768), a potent and selective irreversible inhibitor of type A monoamine oxidase.
abstract: The effects of N-[2-(o-iodophenoxy)ethyl]cyclopropylamine hydrochloride (LY121768) on types A and B monoamine oxidase (MAO) assayed with radiocarbon-labeled serotonin and phenylethylamine, respectively, were studied in vitro and in vivo. Type A MAO from rat brain was inhibited in vitro by LY121768 with an IC50 of 4 x 10(-10) M, whereas 2500 times higher concentrations of LY121768 (IC50 = 1 x 10(-6) M) were required to inhibit type B MAO. The inhibition of type A MAO increased with time of incubation of LY121768 with enzyme prior to substrate addition and persisted after dialysis, indicative of irreversible inhibition. The irreversible inactivation was prevented by harmaline, a reversible, competitive inhibitor of type A MAO, indicating a requirement for catalytic activity of MAO in the time-dependent inactivation by LY121768. In rats, LY121768 selectively inhibited type A MAO in brain and in liver at low doses. The inhibition of type A MAO persisted for several days after a single 10 mg/kg i.p. dose of LY121768 and was associated with a significant increase in brain dopamine, norepinephrine and epinephrine concentrations and a significant decrease in the concentration of the dopamine metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid. The inactivation of type A MAO by LY121768 in vivo was prevented by co-administration of harmaline, indicating a similar mechanism for the in vivo inactivation as for the in vitro inactivation of MAO by LY121768. A reasonable inference from these data and from previous literature is that LY121768 acts as a "suicide substrate" for MAO and inactivates the enzyme by formation of a reactive intermediate which binds covalently to the enzyme. The presence of iodine in the LY121768 molecule not only confers high selectivity for type A MAO but offers a site for radionuclide introduction that might be a useful means of labeling type A MAO in vitro or in vivo for various purposes.
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006246:Harmaline / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; C000434:Lilly 51641; C038033:N-(2-(2-iodophenoxy)ethyl)cyclopropylamine; D006246:Harmaline; D008995:Monoamine Oxidase