title: 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 analogue of 5-methoxy-3-(1,2,5,6-tetrahydropyrid-4-yl)indole.
abstract: The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-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-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents. 3-(1,2,5,6-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-HT1B receptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.
authors.affiliation: Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: J E
authors.initials: JE
authors.lastname: Macor
authors.forename: C A
authors.initials: CA
authors.lastname: Burkhart
authors.forename: J H
authors.initials: JH
authors.lastname: Heym
authors.forename: J L
authors.initials: JL
authors.lastname: Ives
authors.forename: L A
authors.initials: LA
authors.lastname: Lebel
authors.forename: M E
authors.initials: ME
authors.lastname: Newman
authors.forename: J A
authors.initials: JA
authors.lastname: Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Ryan
authors.forename: D W
authors.initials: DW
authors.lastname: Schulz
authors.forename: L K
authors.initials: LK
authors.lastname: Torgersen
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005576:Colforsin / Q000494:pharmacology; D003500:Cyclization; D004435:Eating / Q000187:drug effects; D006168:Guinea Pigs; D006624:Hippocampus / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology*; D015394:Molecular Structure; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D011985:Receptors, Serotonin; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D005576:Colforsin; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D012701:Serotonin