3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) 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(1) receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K(i)=17-23nM) 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+/-4nM. 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.
Huffman
John W
JW
Howard L. Hunter Laboratory, Clemson University, 29634-0973, Clemson, SC, USA. huffman@clemson.edu
Mabon
Ross
R
Wu
Ming Jung
MJ
Lu
Jianzhong
J
Hart
Richard
R
Hurst
Dow P
DP
Reggio
Patricia H
PH
Wiley
Jenny L
JL
Martin
Billy R
BR
D002186:Cannabinoids / Q000737:chemistry / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000378:metabolism; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000737:chemistry / Q000187:drug effects*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002186:Cannabinoids; D003511:Cyclohexanols; D007202:Indicators and Reagents; D007211:Indoles; D008024:Ligands; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol