title: Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.
abstract: In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004837:Epinephrine / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine