The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review.
Since CRH has been shown to mediate stress-induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP-154,526 and its close analog antalarmin are potent, brain-penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP-154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically-administered CP-154,526 has been demonstrated to antagonize CRH- and stress-induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects. These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.
Seymour
Patricia A
PA
CNS Discovery, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., CT 06340, USA. patricia_a_seymour@groton.pfizer.com
Schmidt
Anne W
AW
Schulz
David W
DW
D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001341:Autonomic Nervous System / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy; D004064:Digestive System / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005835:Genitalia / Q000187:drug effects; D000882:Haplorhini; D007107:Immune System / Q000187:drug effects; D051379:Mice; D009048:Motor Skills / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1