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 ligands Original Research Article

Based on the structure of ZK91296 (4d), a high affinity partial agonist of the central benzodiazepine (ω) 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 ω receptor (ω1, ω2, ω5) were determined using rat brain tissue. Practically all of these compounds (except the diethyl ester derivative 22c) showed an approximately twofold selectivity for ω1 (IC50ʹs in the 200–500 nM range) compared to ω2 receptors and practically no affinity for ω5 receptors. Compound 22c showed the highest affinity of all the compounds synthesized (IC50=70 nM for ω1 receptors) as well as a fivefold selectivity for ω1 versus ω2 receptors but also displayed significant binding to ω5 receptors (IC50=250 nM). The absence of appreciable binding of 4-methyl and 4-methoxymethyl derivatives to ω receptors, in contrast to β-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 ω receptor ligands.