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.