PT  - JOURNAL ARTICLE
AU  - Shigeru Okuyama
AU  - Shigeyuki Chaki
AU  - Naoya Kawashima
AU  - Yoshiko Suzuki
AU  - Shin-Ichi Ogawa
AU  - Atsuro Nakazato
AU  - Toshihito Kumagai
AU  - Taketoshi Okubo
AU  - Kazuyuki Tomisawa
TI  - Receptor Binding, Behavioral, and Electrophysiological Profiles of Nonpeptide Corticotropin-Releasing Factor Subtype 1 Receptor Antagonists CRA1000 and CRA1001
DP  - 1999 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 926--935
VI  - 289
IP  - 2
4099  - http://jpet.aspetjournals.org/content/289/2/926.short
4100  - http://jpet.aspetjournals.org/content/289/2/926.full
SO  - J Pharmacol Exp Ther1999 May 01; 289
AB  - Receptor binding, behavioral, and electrophysiological profiles of 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) and 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1001), putative novel and selective antagonists for corticotropin-releasing factor1 (CRF1) receptor were examined. Both CRA1000 and CRA1001 inhibited125I-ovine CRF binding to membranes of rat frontal cortex with IC50 values of 20.6 and 22.3 nM, respectively. Likewise, CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat pituitary. In contrast, both CRA1000 and CRA1001 were without affinity for the CRF2β receptor when examined using rat heart. In mice orally administered CRA1000 and CRA1001 reversed the swim stress-induced reduction of the time spent in the light area in the light/dark exploration task. In nonstress conditions, CRA1000 and CRA1001 were without effect on the time spent in the light area in the same task in mice. Orally administered CRA1000 and CRA1001 dose dependently reversed the effects of i.c.v. infusion of CRF on time spent in the open arms in the elevated plus-maze in rats. Lesioning of olfactory bulbs induced hyperemotionality, and this effect was inhibited by either acute or chronic oral administration of CRA1000 and CRA1001 in rats. The firing rate of locus coeruleus neurons was increased by i.c.v.-infused CRF. This excitation of locus coeruleus neurons was significantly blocked by pretreatment with i.v. administration of CRA1000 and CRA1001. CRA1000 and CRA1001 had no effects on the hexobarbital-induced anesthesia in mice, the rotarod test in mice, the spontaneous locomotor activity in mice, and a passive avoidance task in rats. These observations indicate that both CRA1000 and CRA1001 are selective and competitive CRF1 receptor antagonists with potent anxiolytic- and antidepressant-like properties in various experimental animal models, perhaps through inhibition of CRF1 receptors. CRA1000 and CRA1001 may prove effective for treating subjects with depression- and/or anxiety-related disorders without the side effects seen in the related currently prescribed medications. The American Society for Pharmacology and Experimental Therapeutics