title: Pharmacological comparison of two corticotropin-releasing factor antagonists: in vivo and in vitro studies.
abstract: The present study compared the effects of two analogs of corticotropin-releasing factor (CRF), [D-Phe12,Nle21,38, C alpha MeLeu37]CRF12-41 (D-PheCRF12-41) and alpha helical CRF9-41, as antagonists of CRF in in vivo and in vitro assays. In halothane-anesthetized rats, intracerebroventricular (i.c.v.) administration of both analogs inhibited the activation of locus coeruleus (LC) neuronal discharge produced by CRF (3.0 micrograms, i.c.v.). LC activation by hypotensive stress elicited by intravenous (i.v.) infusion of nitroprusside was antagonized by the same doses of the CRF antagonists that were effective in antagonizing CRF, suggesting that the receptors involved in LC activation by CRF and by hypotensive stress are similar. However, D-PheCRF12-41 was approximately 100 times more potent than alpha helical CRF9-41 when administered i.c.v. The IC50 values for D-PheCRF12-41 as an antagonist of CRF and of nitroprusside were 0.16 and 0.14 microgram, i.c.v., respectively. The IC50 values for alpha helical CRF9-41 as an antagonist of CRF and of nitroprusside were 18 and 27 micrograms, i.c.v., respectively. In contrast, D-PheCRF12-41 was only slightly more potent than alpha helical CRF9-41 in antagonizing CRF-stimulated cyclic AMP production in rat brain homogenates, with IC50s of 78 +/- 15 and 260 +/- 30 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively. Moreover, the antagonists had similar affinities for CRF binding sites in rat brain homogenates, with Kis of 15.5 +/- 4 nM and 10.3 +/- 6 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Mental Health Science, Hahnemann University, Philadelphia, Pennsylvania.
authors.forename: A L
authors.initials: AL
authors.lastname: Curtis
authors.forename: D E
authors.initials: DE
authors.lastname: Grigoriadis
authors.forename: M E
authors.initials: ME
authors.lastname: Page
authors.forename: J
authors.initials: J
authors.lastname: Rivier
authors.forename: R J
authors.initials: RJ
authors.lastname: Valentino
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism
chemical_list: C083591:H-R corticotropin-releasing factor (12-41), Phe(12)-Nle(21,38), C(alpha-MeLeu(37))-; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C113202:phenylalanyl corticotropin-releasing factor (12-41); D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41); D000262:Adenylyl Cyclases