3-Indolyl-1-naphthylmethanes: New Cannabimimetic Indoles. Provide Evidence for Aromatic Stacking Interactions with the. CB1 Cannabinoid Receptor

Authors

John W. Huffman, Clemson University
Ross Mabon, Clemson University
Ming-Jung Wu, Clemson University
Jianzhong Lu, Clemson University
Richard E. Hart, Kennesaw State UniversityFollow
Dow P. Hurst, Kennesaw State University
Patricia H. Reggio, Kennesaw State UniversityFollow
Jenny L. Wiley, Medical College of Virginia
Billy R. Martin, Medical College of VirginiaFollow

Document Type

Article

Publication Date

2-2003

Abstract

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 CB₁ 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.