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Vol. 286, Issue 2, 913-924, August 1998
Preclinical CNS Research Department (J.R.M., M.B., F.J., J.-L.M.,
V.M., A.J.S., J.W., C.K.), Pharma Division, F. Hoffmann-La Roche Ltd.,
Basel, Switzerland and
Department of Neuropharmacology (J.S.A.,
H.H.G.B., C.L.E.B., G.S.F.R., A.M.L.D.), N.V. Organon, Oss, The
Netherlands
In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine
1:1 C4H4O4 and
(S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity
binding to the serotonin2C (5HT2C) receptors
and stimulated turnover of inositol 1,4,5-triphosphate. Affinity to
several of the other 5-HT receptor subtypes and to numerous
nonserotonergic receptors was much lower. In rats, both compounds
elicited behavioral signs of 5-HT2C receptor agonism but
not 5-HT2A receptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2C
receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-urea 1:1 HCI. In
addition, these compounds were active in tests used to demonstrate
anticompulsive effects: reducing schedule-induced polydipsia in rats
(prevented by the 5-HT2C/2B receptor antagonist
N-(1-methyl-5'-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased
scratching induced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in
squirrel monkeys (no tolerance developed), decreasing responding in the
marble-burying task in mice, and decreasing excessive eating of
palatable food in rats. In contrast to these compounds, fluoxetine was
much less potent, and in some tasks less efficacious, in reducing
excessive behavior in these models. These two 5-HT2C
receptor agonists do not show anxiogenic effects in the plus-maze in
rats.
(S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 reduced the olfactory
bulbectomy-induced passive avoidance impairment in rats, a result that
indicates antidepressant potential. Similarly, in the
differential-reinforcement-of-low rate 72-s operant schedule task in
rats, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1
C4H4O4 increased (and
(S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to
increase) total reinforcements received, which is suggestive of
antidepressant activity. The electroencephalography defined
sleep-waking pattern in rats produced by these two 5-HT2C
agonists, as well as fluoxetine, included increased quiet-waking and
decreased rapid-eye-movement sleep, which is characteristic of
antidepressant drugs. These results suggest that 5-HT2C
receptor agonism is associated with therapeutic potential in obsessive
compulsive disorder and depression.
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