PHARMACOLOGICAL PROFILE OF THE NOVEL ANTIDEPRESSANT 6-METHYL-2-(1-PIPERAZINYL)THIENO-[2,3-D]PYRIMIDINE MONOHYDRATE HYDROCHLORIDE

This is a first report on the investigation of the antidepressant acti vity of MCI-225 -6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine mon ohydrate hydrochloride, CAS 99487-26-0) in comparison with maprotiline (GAS 10347-81-6), desipramine (GAS 58-28-6), imipramine (GAS 113-52-0 ) and trazodone (GAS 25332-39-2). MCI-225 inhibited the synaptosomal u ptake of noradrenaline (NA, K-i = 35.0 nmol/l), serotonin (5-HT, K-i = 491 nmol/l), and dopamine (K-i = 14800 nmol/l), although it did not i nhibit MAO-A and MAO-B activities. MCI-225 showed high affinity only f or the 5-HT3 receptor (K-i = 81.0 nmol/l) among all receptors tested i ncluding M-1, M-2, alpha(1), and H-1 receptors. The inhibition of the von Bezold-Jarisch reflex by MCI-225 (ID50 = 22.2 mg/kg, p.o.) suggest s its antagonistic action on the 5-HT3 receptor. MCI-225 dose-dependen tly reduced reserpine-induced hypothermia (0.3-10 mg/kg, p.o.) and pot entiated yohimbine-induced lethality (3-100 mg/kg, p.o.) in mice. Thes e effects of MCI-225 were as potent as desipramine and more potent tha n maprotiline, imipramine and trazodone. MCI-225 and desipramine did n ot change either 5-HTP-induced head movements or p-CA-induced hyperact ivity 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. M CI-225 (10 mg/kg, p.o.) decreased the REM sleep period without affecti ng slow-wave sleep or wakefulness in rats. Even at 100 mg/kg, p.o. MCI -225 and trazodone did not inhibit oxotremorine-induced tremor, lacrim ation or salivation in mice in contrast with imipramine. These results suggest that MCI-225, which selectively inhibits NA uptake and antago nizes the 5-HT3 receptor, has potential as a new type of potent antide pressant.