title: 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.affiliation: Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. stephen.heinrichs@bc.edu
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Heinrichs
authors.forename: Errol B
authors.initials: EB
authors.lastname: De Souza
authors.forename: Gery
authors.initials: G
authors.lastname: Schulteis
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Lapsansky
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013312:Stress, Physiological / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
chemical_list: D014151:Anti-Anxiety Agents; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone