Michikazu Abe (1), Hiroshi Nakai(2), Reiko Tabata (1), Ken-Ichi Saito
(1) and Mitsuo Egawa (3)
(1) Pharmaceuticals Laboratory I, (2) Pharmacokinetics and Metabolism
Research Laboratory, Yokohama Research Center, Mitsubishi Chemical Corporation,
1000, Kamoshida, Aoba-ku, Yokohama 227-8502, Japan
(3) Clinical Research Department, Mitsubishi Chemical Corporation, Shinagawa-ku,
Tokyo 140-0002, Japan
Abstract: Behavioral effects of 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole
HCI (MKC-242), a novel 5-HT1A-receptor agonist, were evaluated
using animal models of anxiety and obsessive compulsive disorder and compared
against reference compounds. MKC-242 suppressed foot shock-induced fighting
behavior without loss of motor coordination in mice as the reference compounds
did. The ED50 values of MKC-242, buspirone, tandospirone and
diazepam were 1.7, 42, 80 and 2.0 mg/kg, p.o., respectively. The duration
of the suppression of fighting by MKC-242 was longer than those of buspirone
and tandospirone and comparable to that of diazepam. Similar results were
also obtained with the water-lick conflict test in rats. The plasma concentration
of MKC-242 in rats was much higher than the reported value of buspirone
during 0.25 - 6 hr after oral administration. In addition, MKC-242 reduced
marble burying behavior without reduction of motor activity. Fluoxetine,
tandospirone and diazepam also reduced the behavior at non-sedative doses.
These findings indicate that MKC-242 possesses a longer-lasting anxiolytic
effect than azapirones. This might be due to the high concentration of the
compound in plasma. In addition, it is also suggested that MKC-242 possesses
an antiobsessional effect.
Keywords: MKC-242, 5-HT1A receptor, Anxiolytic, Aggressive
behavior, Marble burying behavior