This is a first report on the investigation of the antidepressant activity of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride, CAS 99487-26-0) in comparison with maprotiline (CAS 10347-81-6), desipramine (CAS 58-28-6), imipramine (CAS 113-52-0) and trazodone (CAS 25332-39-2). MCI-225 inhibited the synaptosomal uptake of noradrenaline (NA, Ki = 35.0 nmol/l), serotonin (5-HT, Ki = 491 nmol/l), and dopamine (Ki = 14,800 nmol/l), although it did not inhibit MAO-A and MAO-B activities. MCI-225 showed high affinity only for the 5-HT3 receptor (Ki = 81.0 nmol/l) among all receptors tested including M1, M2, alpha 1, and H1 receptors. The inhibition of the von Bezold-Jarisch reflex by MCI-225 (ID50 = 22.2 mg/kg, p.o.) suggests its antagonistic action on the 5-HT3 receptor. MCI-225 dose-dependently reduced reserpine-induced hypothermia (0.3-10 mg/kg, p.o.) and potentiated yohimbine-induced lethality (3-100 mg/kg, p.o.) in mice. These effects of MCI-225 were as potent as desipramine and more potent than maprotiline, imipramine and trazodone. MCI-225 and desipramine did not change either 5-HTP-induced head movements or p-CA-induced hyperactivity in rats. In forced swimming tests in rats, the minimum effective doses of MCI-225, maprotiline, desipramine, and imipramine were 1, 30, 10 and 30 mg/kg, p.o., respectively, for 5-days administration. Only MCI-225 had shown its full activity with this short term treatment. MCI-225 (10 mg/kg, p.o.) decreased the REM sleep period without affecting slow-wave sleep or wakefulness in rats. Even at 100 mg/kg, p.o. MCI-225 and trazodone did not inhibit oxotremorine-induced tremor, lacrimation or salivation in mice in contrast with imipramine. These results suggest that MCI-225, which selectively inhibits NA uptake and antagonizes the 5-HT3 receptor, has potential as a new type of potent antidepressant.
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