Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist.

Abstract

The present studies were designed to evaluate the competitive binding properties and functional effects of a novel nonpeptide CRF1 receptor antagonist, R121919. R121919 administered in doses of 0.63 to 20 mg/kg p.o. 60 min pretest in Wistar rats dose dependently attenuated the swim stress-induced anxiogenic-like behavior in the elevated plus-maze model of anxiety. Moreover, receptor autoradiography revealed that R121919 dose-dependently occupied brain CRF1 receptors in subjects tested in the plus-maze experiment. Orally administered doses of up to 20 mg/kg R121919 also blunted basal and swim stress-induced pituitary-adrenocortical activation, produced additional anxiolytic-like behavioral actions in the defensive withdrawal and defensive burying paradigms, and functionally antagonized the locomotor stimulatory properties of exogenously administered CRF. Taken together, these results suggest that the anxiolytic-like efficacy of R121919 in attenuating the stress-, novelty-, shock-, and CRF-induced increases in behavioral arousal is correlated with competitive blockade of central CRF1 receptors.

• Authors: Stephen C Heinrichs, Errol B De Souza, Gery Schulteis, Jeanette L Lapsansky, Dimitri E Grigoriadis
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 27 Issue 2 Pg. 194-202 (Aug 2002) ISSN: 0893-133X [Print] England
• PMID: 12093593 (Publication Type: Journal Article)

Chemical References

• Anti-Anxiety Agents
• Pyrimidines
• R 121919
• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1
• Adrenocorticotropic Hormone
• Corticotropin-Releasing Hormone
• Corticosterone

Topics

• Adrenocorticotropic Hormone (blood)
• Animals
• Anti-Anxiety Agents (pharmacokinetics)
• Anxiety (drug therapy, metabolism, physiopathology)
• Behavior, Animal (drug effects, physiology)
• Binding Sites (drug effects, physiology)
• Binding, Competitive (drug effects, physiology)
• Brain (drug effects, metabolism, physiopathology)
• Corticosterone (blood)
• Corticotropin-Releasing Hormone (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions (physiology)
• Male
• Maze Learning (drug effects, physiology)
• Pituitary-Adrenal System (drug effects, physiology)
• Pyrimidines (pharmacokinetics)
• Rats
• Rats, Wistar
• Reaction Time (drug effects, physiology)
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors, metabolism)
• Stress, Physiological (drug therapy, metabolism, physiopathology)