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.
MeSH terms
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Acoustic Stimulation
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Adenylyl Cyclases / metabolism
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Adrenocorticotropic Hormone / blood
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Adrenocorticotropic Hormone / metabolism*
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Animals
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Binding, Competitive
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Callithrix
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Cell Line
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Cell Membrane / enzymology
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Cerebral Cortex / enzymology
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Cerebral Ventricles / drug effects
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Cerebral Ventricles / physiology*
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Corticotropin-Releasing Hormone / administration & dosage
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Corticotropin-Releasing Hormone / pharmacology*
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Dogs
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Guinea Pigs
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Humans
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Injections, Intraventricular
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Kinetics
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Locus Coeruleus / physiology*
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Male
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Neurons / drug effects
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Neurons / physiology*
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Pituitary Gland / enzymology
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Pyrimidines / administration & dosage
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Pyrroles / administration & dosage
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
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Receptors, Corticotropin-Releasing Hormone / metabolism*
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Reflex, Startle / drug effects*
Substances
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CP 154526
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Pyrimidines
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Pyrroles
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Receptors, Corticotropin-Releasing Hormone
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Adrenocorticotropic Hormone
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Corticotropin-Releasing Hormone
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Adenylyl Cyclases