title: Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.
abstract: In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor.
authors.affiliation: Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA. huffman@clemson.edu
authors.forename: John W
authors.initials: JW
authors.lastname: Huffman
authors.forename: Gulay
authors.initials: G
authors.lastname: Zengin
authors.forename: Ming-Jung
authors.initials: MJ
authors.lastname: Wu
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Lu
authors.forename: George
authors.initials: G
authors.lastname: Hynd
authors.forename: Kristen
authors.initials: K
authors.lastname: Bushell
authors.forename: Alicia L S
authors.initials: AL
authors.lastname: Thompson
authors.forename: Simon
authors.initials: S
authors.lastname: Bushell
authors.forename: Cindy
authors.initials: C
authors.lastname: Tartal
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cassidy
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Billy R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000478:Alkylation; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)