SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. II. Biochemical characterization of monoamine oxidase inhibition.
SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide. Ex vivo, SR 95191 also preferentially inhibited MAO-A in the brain and was 6 and 13 times less potent than cimoxatone and moclobemide, respectively. Like all MAO-A inhibitors, SR 95191 in vivo caused a dose-dependent increase in striatal 3-methoxytyramine, dopamine, serotonin and in hypothalamic norepinephrine contents. A concomitant decrease in deaminated metabolites was observed. SR 95191 inhibited peripheral MAO activity in liver and duodenum. In brain, liver and duodenum, MAO inhibition induced by SR 95191 was short-lasting. Repeated dosing for 14 days did not enhance MAO-A inhibition. Like all reversible MAOIs, SR 95191 antagonized the long-lasting MAO-A inhibition induced by clorgyline. Finally, SR 95191 did not affect monoamine uptake either in vitro or in vivo and did not interact in vitro with a variety of neurotransmitter or drug receptor sites. Based on these results it is postulated that SR 95191 is a selective and reversible type A MAOI of medium potency, which may be of therapeutic benefit in depressed patients.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D004386:Duodenum / Q000201:enzymology; D006246:Harmaline / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D020912:Moclobemide; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology; D023303:Oxazolidinones; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D012642:Selegiline / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology
D001549:Benzamides; D001679:Biogenic Amines; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D011724:Pyridazines; D012642:Selegiline; C051273:SR 95191; D006246:Harmaline; D008995:Monoamine Oxidase; D003010:Clorgyline; D020912:Moclobemide; C026234:cimoxatone; D004298:Dopamine