The Pharmacology of CP‐154,526, a Non‐Peptide Antagonist of the CRH1 Receptor: A Review

Abstract

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.

Corticotropin-releasing factor receptors and stress-related alterations of gut motor function

“…These small-molecular weight compounds cross the blood-brain barrier with a penetrance largely influenced by their distinct physicochemical properties, particularly their lipophilicity (35). Among the selective CRF 1 antagonists, CP-154,526, antalarmin, DPM696, NBI 30775 (also known as R121919), and NBI 35965 have been among the most commonly used and characterized (35,45,46) (Figure 1). With the availability of selective CRF receptor antagonists, it has become clear that the constellation of physiological effects produced by endogenous CRF peptides might be attributed to actions on distinct CRF receptor subtypes.…”

Pharmacogenetics of antidepressant response

“…[319][320][321] Some evidence stands for a relevance of CRHR1 variants and antidepressant response, in particular an association within the rs242941 GG genotype and homozygous GAG haplotype of the 3 SNPs (rs1876828, rs242939 and rs242941) and therapeutic response to fluoxetine. 322,323 Moreover, rs110402 has been found to be associated with increased risk to present a seasonal pattern and early onset of the first depressive episode.…”

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

“…The selective CRF 1 receptor antagonist (butylethyl [2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine) hydrochloride (Chen et al 1997;Seymour et al 2003) was a generous gift from Pfizer, Inc. (Groton, CT) and was dissolved in sterile water containing 0.1% (v/v) acetic acid prior to dilution to the appropriate concentration in aCSF. The selective CRF 2 receptor antagonist antisauvagine-30 (AS30, (Ruhmann et al 1998) was obtained from Polypeptide Laboratories (Torrance, CA) and dissolved in aCSF.…”