3-(1,2,5,6-TETRAHYDROPYRID-4-YL)PYRROLO[3,2-B]PYRID-5-ONE - A POTENT AND SELECTIVE SEROTONIN (5-HT1B) AGONIST AND ROTATIONALLY RESTRICTED PHENOLIC ANALOG OF 5-METHOXY-3-(1,2,5,6-TETRAHYDROPYRID-4-YL)INDOLE

The synthesis and in vitro and in vivo characteristics of 3-(l,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1Areceptor, 150x vs the 5HT1Dreceptor) functional agonist for the 5-HT1Breceptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1Breceptors in regulating feeding behavior in rodents. 3-(l,2,5,6-Tetrahydropyrid-4-yl)pyrrolo-[3,2-b]pyrid-5-one (1) has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1Breceptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-5]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole. © 1990, American Chemical Society. All rights reserved.