Studies on adrenal phenylethanolamine N- methyltransferase (PNMT) with S K & F 64139, a selective inhibitor.
SK&F 64139 is a potent, reversible inhibitor of phenylethanolamine N-methyltransferase; its IC50 concentration in our standard assay system was 1 X 10(-7) M. Kinetically, the compound is a competitive inhibitor with respect to norepinephrine but is uncompetitive when S-adenosylmethionine is the variable substrate. In contrast to a previously reported compound (SK&F 7698), the drug is only a weak alpha receptor antagonist (KB = 6 X 10(-6) M). In both the rat and squirrel monkey, SK&F 64139 produced dose-dependent decreases in the adrenal epinephrine content coupled with stoichiometrically equivalent increases in the norepinephrine pool(s). Further evidence for in vivo phenylethanolamine N-methyltransferase inhibitory activity was that the drug markedly inhibited the conversion of a tracer dose of 3H-norepinephrine to 3H-epinephrine in the rat adrenal gland after unit oral doses as low as 5 mg/kg.
D000311:Adrenal Glands / Q000201:enzymology*; D000317:Adrenergic alpha-Antagonists; D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D004837:Epinephrine / Q000096:biosynthesis; D005260:Female; D000882:Haplorhini; D007546:Isoquinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors; D009638:Norepinephrine / Q000378:metabolism; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects; D012453:Saimiri
D000317:Adrenergic alpha-Antagonists; D065098:Catechol O-Methyltransferase Inhibitors; D007546:Isoquinolines; D008996:Monoamine Oxidase Inhibitors; D011941:Receptors, Adrenergic; D008995:Monoamine Oxidase; D010625:Phenylethanolamine N-Methyltransferase; D009638:Norepinephrine; D004837:Epinephrine