5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrroloindole: A Novel 5-HT2C/5-HT2B Receptor Antagonist with Improved Affinity, Selectivity, and Oral Activity

Article abstract of DOI:10.1021/jm00014a004

The preparation of a series of conformationally restricted analogues of indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrroloquinolines, is described.The binding affinities of these compounds at 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors were determined.Of these compounds, the 1,2,3,5-tetrahydropyrrolo<2.3-f>indole derivative, compound 11, was found to have high affinity for the 5-HT_2C (pK₁ 8.0) and 5-HT_2B receptors (pA₂ 8.5), with excellent selectivity over the 5-HT_2A and various other receptors (pK₁<6). 11 is also considerably more activethan 1 in both an in vitro functional model, 5-HT-stimulated phosphoinositol hydrolysis (pK_B 8.8), and an in vivo functional model, mCPP-induced hypolocomotion (ID₅₀ 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the functional significance of blockade of 5-HT_2B and 5-HT_2C receptors.