title: In vitro pharmacological profile of nonpeptide CRF1 receptor antagonists, CRA1000 and CRA1001.
abstract: We investigated pharmacological properties of CRA1000 (2-(N-(2-methylthio-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluoro phenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine) and CRA1001 (2-( N-(2-bromo-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluorophenyl)-1 ,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine), novel and selective antagonists for the corticotropin-releasing factor1 (CRF1) receptor. Both CRA1000 and CRA1001 inhibited [125I]ovine CRF binding to membranes of COS-7 cells expressing the rat CRF1 receptor with IC50 values of 30 and 38 nM, respectively, without affecting [125I]sauvagine binding to membranes of COS-7 cells expressing the rat CRF2alpha receptor. CRF elicited intracellular cyclic AMP (cAMP) accumulation in AtT-20 cells which express the CRF1 receptor but not the CRF2 receptor, and COS-7 cells expressing CRF1 or CRF2alpha receptors. The CRF-induced cAMP accumulation was inhibited by both CRA1000 and CRA1001, concentration-dependently, in AtT-20 cells and COS-7 cells expressing the CRF1 receptor, while these compounds did not attenuate the CRF response in COS-7 cells expressing the CRF2alpha receptor. CRF increased adrenocorticotropin (ACTH) secretion from AtT-20 cells, and CRA1000 and CRA1001 inhibited CRF-induced ACTH secretion, concentration-dependently, as did other CRF1 receptor antagonists. These results show that both CRA1000 and CRA1001 are potent and selective CRF1 receptor antagonists.
authors.affiliation: 1st Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical, Ohmiya, Saitama, Japan. s13555@ccm.taisho.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Chaki
authors.forename: S
authors.initials: S
authors.lastname: Okuyama
authors.forename: A
authors.initials: A
authors.lastname: Nakazato
authors.forename: T
authors.initials: T
authors.lastname: Kumagai
authors.forename: T
authors.initials: T
authors.lastname: Okubo
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Oshida
authors.forename: Y
authors.initials: Y
authors.lastname: Hamajima
authors.forename: K
authors.initials: K
authors.lastname: Tomisawa
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019556:COS Cells / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005625:Frontal Lobe / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C118847:CRA 1001; D011725:Pyridines; D011743:Pyrimidines; C117406:CRA1000; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP