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Vol. 289, Issue 2, 926-935, May 1999
1st Laboratory, Medicinal Research Laboratories, Taisho
Pharmaceutical Co., Ltd. 1-403, Yoshino-cho, Ohmiya, Saitama, Japan
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 inhibited
125I-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 CRF2
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.
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