STUDIES ON ADRENAL PHENYLETHANOLAMINE N-METHYLTRANSFERASE (PNMT) WITH SK AND F64139, A SELECTIVE INHIBITOR

Abstract

SK&F 64139 [7,8-dichloro-1,2,3,4-tetrahydroisoquinoline] is a potent, reversible inhibitor of phenylethanolamine N-methyltransferase; its IC50 [median inhibitory concentration] concentration by the standard assay system was 1 .times. 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 [3-methyl-1,2,3,4-tetrahydro-[1]benzthieno[3,2-c]pyridine hydrochloride] (SK&F 7698), the drug is only a weak .alpha.- receptor antagonist (KB = 6 .times. 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.