LCARBAMOYL)-1,2,3,5-TETRAHYDROPYRROLO[2,3-F]INDOLE - A NOVEL 5-HT2C 5-HT2B RECEPTOR ANTAGONIST WITH IMPROVED AFFINITY, SELECTIVITY, AND ORAL ACTIVITY

The preparation of a series of conformationally restricted analogues o f indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrrolo quinolines, is described. The binding affinities of these compounds at 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined. Of these compou nds, the 1,2,3,5-tetrahydropyrrolo[2,3-f]indole derivative, compound 1 1, was found to have high affinity for the 5-HT2C (pK(I) 8.0) and 5-HT 2B receptors (pA(2) 8.5), with excellent selectivity over the 5-HT2A a nd various other receptors (pK(I) <6). 11 is also considerably more ac tive than 1 in both an in vitro functional model, 5-HT-stimulated phos phoinositol hydrolysis (pK(B) 8.8), and an in vivo functional model, m CPP-induced hypolocomotion (ID50 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the fun ctional significance of blockade of 5-HT2B and 5-HT2C receptors.