J. Eguchi et al., PHARMACOLOGICAL PROFILE OF THE NOVEL ANTIDEPRESSANT 6-METHYL-2-(1-PIPERAZINYL)THIENO-[2,3-D]PYRIMIDINE MONOHYDRATE HYDROCHLORIDE, Arzneimittel-Forschung, 47(12), 1997, pp. 1337-1347
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.