CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.
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.
Schulz
D W
DW
Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA.
Mansbach
R S
RS
Sprouse
J
J
Braselton
J P
JP
Collins
J
J
Corman
M
M
Dunaiskis
A
A
Faraci
S
S
Schmidt
A W
AW
Seeger
T
T
Seymour
P
P
Tingley
F D
FD
Winston
E N
EN
Chen
Y L
YL
Heym
J
J
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*
C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000262:Adenylyl Cyclases