3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB 1 cannabinoid receptor

Abstract

A series of 1-pentyl-1 H-indol-3-yl-(1-naphthyl)methanes ( 9– 11) and 2-methyl-1-pentyl-1 H-indol-3-yl-(1-naphthyl)methanes ( 12– 14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB 1 receptor by hydrogen bonding to the carbonyl group. Indoles 9– 11 have significant ( K i=17–23 nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles ( 5, 15, 16). 2-Methyl-1-indoles 12– 14 have little affinity for the CB 1 receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17– 19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon ( 26) was synthesized and found to have K i=26±4 nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener ( 19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB 1 receptor.