5-HT2C RECEPTOR AGONISTS - PHARMACOLOGICAL CHARACTERISTICS AND THERAPEUTIC POTENTIAL

In vitro, -2-(chloro-5-fluoro-indol-1-yl)-1-methylethyiamine 1:1 C4H4O 4 and hydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 ex hibited high-affinity binding to the serotonin,, (5HT(2C)) receptors a nd stimulated turnover of inositol 1,4,5-triphosphate. Affinity to sev eral of the other 5-HT receptor subtypes and to numerous nonserotonerg ic receptors was much lower. In rats, both compounds elicited behavior al signs of 5-HT2C receptor agonism but not 5-HT2A receptor agonism. H ypomotility induced in rats by high doses of these compounds was rever sed by the 5-HT,, receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-ur ea 1:1 HCl. In addition, these compounds were active in tests used to demonstrate anticompulsive effects: reducing schedule-induced polydips ia in rats (prevented by the 5-HT2C/2B receptor antagonist N-(1-methyl -5'-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased scratching i nduced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in squirrel monkey s (no tolerance developed), decreasing responding in the marble-buryin g task in mice, and decreasing excessive eating of palatable food in r ats. 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 anxiogeni c effects in the plus-maze in rats. hydro-indeno[1,2-b]pyrrol-1-yl)-1- methylethylamine 1:1 C4H4O4 reduced the olfactory bulbectomy-induced p assive avoidance impairment in rats, a result that indicates antidepre ssant potential. Similarly, in the differential-reinforcement-of-low r ate 72-s operant schedule task in rats, -2-(chloro-5-fluoro-indol-1-yl )-1-methylethylamine 1:1 C4H4O4 increased (and hydro-indeno[1,2-b]pyrr ol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to increase) total reinforcements received, which is suggestive of antidepressant a ctivity. The electroencephalography defined sleep-waking pattern in ra ts produced by these two 5-HT2C agonists, as well as fluoxetine, inclu ded increased quiet-waking and decreased rapid-eye-movement sleep, whi ch is characteristic of antidepressant drugs. These results suggest th at 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.