Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001

Receptor binding, behavioral, and electrophysiological profiles of 2-[N-(2- methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-t etrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) and 2-[N-(2-bromo-4-iso propylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin -1-yl)-6-methylpyrimidine (CRA1001), putative novel and selective antagonis ts for corticotropin-releasing factor(1) (CRF1) receptor were examined. Bot h CRA1000 and CRA1001 inhibited I-125-ovine CRF binding to membranes of rat frontal cortex with IC50 values of 20.6 and 22.3 nM, respectively. Likewis e, CRA1000 and CRA1001 inhibited I-125-ovine CRF binding to membranes of ra t pituitary. In contrast, both CRA1000 and CRA1001 were without affinity fo r the CRF2 beta receptor when examined using rat heart. In mice orally admi nistered CRA1000 and CRA1001 reversed the swim stress-induced reduction of the time spent in the light area in the light/dark exploration task. In non stress conditions, CRA1000 and CRA1001 were without effect on the time spen t in the light area in the same task in mice. Orally administered CRA1000 a nd 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 inhibite d 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.-in fused CRF. This excitation of locus coeruleus neurons was significantly blo cked by pretreatment with i.v, administration of CRA1000 and CRA1001. CRA10 00 and CRA1001 had no effects on the hexobarbital-induced anesthesia in mic e, the rotarod test in mice, the spontaneous locomotor activity in mice, an d a passive avoidance task in rats. These observations indicate that both C RA1000 and CRA1001 are selective and competitive CRF, receptor antagonists with potent anxiolytic- and antidepressant-like properties in various exper imental animal models, perhaps through inhibition of CRF, receptors. CRA100 0 and CRA1001 may prove effective for treating subjects with depression- an d/or anxiety-related disorders without the side effects seen in the related currently prescribed medications.