Synthesis and benzodiazepine receptor (ω receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of ω1 selective ligands1This article is dedicated to the memory of our friend and colleague, Sir Derek Barton.1

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]pyridine-5-carboxylate derivatives having mainly aralkyl and aralkyloxy substituents at C-3 was synthesized. The in vitro binding affinities of these compounds for three subclasses of the omega receptor (omega(1), omega(2), omega(5)) were determined using rat brain tissue. Practically all of these compounds (except the diethyl ester derivative 22c) showed an approximately twofold selectivity for omega(1) (IC50's in the 200-500 nM range) compared to omega(2) receptors and practically no affinity for omega(5) receptors. Compound 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 omega(5) receptors (IC50 = 250 nM:). The absence of appreciable binding of 4-methyl and 4-methoxymethyl derivatives to omega receptors, in contrast to beta-carbolines having these similarly located substituents, suggests that the 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.