| Abstrakt: |
In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4exhibited 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-HT2Creceptor agonism but not 5-HT2Areceptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2Creceptor 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/2Breceptor 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-HT2Creceptor 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 C4H4O4reduced 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 C4H4O4increased (and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4showed 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-HT2Cagonists, 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-HT2Creceptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression. |
