Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of omega1 selective ligands

• Published in: Bioorganic & medicinal chemistry 1999-05, Vol.7 (5), p.921
• Main Authors: Doisy, X, Dekhane, M, Le Hyaric, M, Rousseau, J F, Singh, S K, Tan, S, Guilleminot, V, Schoemaker, H, Sevrin, M, George, P, Potier, P, Dodd, R H
• Format: Article
• Language: English
• Subjects: Animals; Brain - drug effects; Carbolines - chemical synthesis; Carbolines - pharmacology; In Vitro Techniques; Inhibitory Concentration 50; Models, Chemical; Models, Molecular; Pyridines - chemical synthesis; Pyrroles - chemical synthesis; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism
• ISSN: 0968-0896

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 (omega1, omega2, omega5) were determined using rat brain tissue. Practically all of these compounds (except the diethyl ester derivative 22c) showed an approximately twofold selectivity for omega1 (IC50's in the 200-500 nM range) compared to omega2 receptors and practically no affinity for omega5 receptors. Compound 22c showed the highest affinity of all the compounds synthesized (IC50 = 70 nM for omega1 receptors) as well as a fivefold selectivity for omega1 versus omega2 receptors but also displayed significant binding to omega5 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.