Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo [2,3-c]pyridine-5-carboxylate, a novel class of omega(1) selective ligands

Based on the structure of ZK91296 (4d), a high affinity partial agonist of the central benzodiazepine (omega) receptor, a series of pyrrolo[2,3-c]pyri dine-5-carboxylate derivatives having mainly aralkyl and aralkyloxy substit uents at C-3 was synthesized. The in vitro binding affinities of these comp ounds for three subclasses of the omega receptor (omega(1), omega(2), omega (5)) were determined using rat brain tissue. Practically all of these compo unds (except the diethyl ester derivative 22c) showed an approximately twof old selectivity for omega(1) (IC50's in the 200-500 nM range) compared to o mega(2) receptors and practically no affinity for omega(5) receptors. Compo und 22c showed the highest affinity of all the compounds synthesized (IC50 = 70 nM for omega(1) receptors) as well as a fivefold selectivity for omega (1) versus omega(2) receptors but also displayed significant binding to ome ga(5) receptors (IC50 = 250 nM:). The absence of appreciable binding of 4-m ethyl and 4-methoxymethyl derivatives to omega receptors, in contrast to be ta-carbolines having these similarly located substituents, suggests that th e pyrrolo[2,3-c]pyridine-5-carboxylates may be considered an entirely novel class of selective omega receptor ligands. (C) 1999 Elsevier Science Ltd. All rights reserved.