3-Indolyl-1-naphthylmethanes: New Cannabimimetic Indoles Provide Evidence for Aromatic Stacking Interactions with the CB 1 Cannabinoid Receptor John W. Huffman, a, * Ross Mabon, a Ming-Jung Wu, a Jianzhong Lu, a Richard Hart, b Dow P. Hurst, b Patricia H. Reggio, b Jenny L. Wiley c and Billy R. Martin c a Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA b Department of Chemistry and Biochemistry, Kennesaw State University, 1000 Chastain Road, Kennesaw, GA 30144, USA c Department of Pharmacology and Toxicology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, VA 23298-0613, USA Received 17 June 2002; accepted 9 September 2002 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 CB 1 receptor by hydrogen bonding to the carbonyl group. Indoles 9–11 have significant (K i =17–23 nM) receptor affinity, some- what 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 cannabi- mimetic 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. # 2002 Elsevier Science Ltd. All rights reserved. Introduction Following the identification of Á 9 -tetrahydrocanna- binol (Á 9 -THC, 1) 1 as the principal psychoactive con- stituent of marijuana, a comprehensive set of structure– activity relationships (SAR) was developed based upon the partially reduced dibenzopyran structure of Á 9 -THC. 2 6 These SAR were subsequently extended to a group of very potent non-traditional cannabinoids developed by Pfizer, of which CP-55,940 (2, DMH=1,1-dimethylheptyl) is typical. 7,8 In 1991, as a result of a program directed toward the development of nonsteroidal anti-inflammatory drugs, a group at Sterling Winthrop reported that pravadoline (3) unexpectedly inhibited contractions of the elec- trically stimulated mouse vas deferens. 9 It was found that 3 and related compounds also inhibit adenylate cyclase, are antinociceptive in vivo and interact with a G-protein coupled receptor in the brain. Work from the same group confirmed that these aminoalkylindoles (AAIs) bind to the cannabinoid receptor which is expressed primarily in the central nervous system (CB 1 0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(02)00451-0 Bioorganic & Medicinal Chemistry 11 (2003) 539–549 *Corresponding author. Fax: +1-864-656-6613; e-mail: huffman@ clemson.edu