Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

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.

Synthesis and biological properties of some novel heterocyclic homoprostanoids.

In the search for prostaglandin-like structures capable of exerting specific and desirable biological properties, a variety of simple heterocyclic homoprostanoidal derivatives was synthesized from readily available stearic acid derivatives. Compounds 5b and 5e were found to be more than 100 times as potent as PGE1 and PGE2 in a tracheal chain bioassay and, like 6, 9, and 12, inhibited PGE2-induced diarrhea. Derivatives 6 and 7a showed significant PG-synthetase inhibitor activity.