CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.
Proceedings of the National Academy of SciencesPublished 17 September 1996Open access
David W. Schulz, Robert S. Mansbach, Jeffrey Sprouse, John P. Braselton, J.L. Collins, Michael L. Corman
Citations379
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TL;DR
It is proposed 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.
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.
Keywords
MedicineNeuroscience
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The Journal of Clinical Endocrinology & MetabolismHypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls.
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Data from pharmacological studies indicated that the ability of a variety of CRF fragments and analogs to inhibit 125I-rCRF to olfactory bulb membranes correlates well with their reported relative potencies in stimulating pituitary adrenocorticotropic hormone secretion in vitro.
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The results suggest that CRF has “anxiogenic” properties and may serve as a neuroendocrine modulator of stress-enhanced behaviors.
PubMedCorticotropin-releasing factor and behavior.
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Results suggest that CRF liberated directly into the central nervous system may have a neurotropic action important for mobilizing behavioral responses to stress.
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