3-indolyl-1-naphthylmethanes:: New cannabimimetic Indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor

A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9 11) and 2-methyl-1-pentyl-1H-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 I 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 CB1 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 CB1 receptor. (C) 2002 Elsevier Science Ltd. All rights reserved.