title: CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.
abstract: Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.
authors.affiliation: Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Schulz
authors.forename: R S
authors.initials: RS
authors.lastname: Mansbach
authors.forename: J
authors.initials: J
authors.lastname: Sprouse
authors.forename: J P
authors.initials: JP
authors.lastname: Braselton
authors.forename: J
authors.initials: J
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Corman
authors.forename: A
authors.initials: A
authors.lastname: Dunaiskis
authors.forename: S
authors.initials: S
authors.lastname: Faraci
authors.forename: A W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: T
authors.initials: T
authors.lastname: Seeger
authors.forename: P
authors.initials: P
authors.lastname: Seymour
authors.forename: F D
authors.initials: FD
authors.lastname: Tingley
authors.forename: E N
authors.initials: EN
authors.lastname: Winston
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Heym
mesh_terms: D000161:Acoustic Stimulation; D000262:Adenylyl Cyclases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002144:Callithrix; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007276:Injections, Intraventricular; D007700:Kinetics; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010902:Pituitary Gland / Q000201:enzymology; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects*
chemical_list: C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000262:Adenylyl Cyclases