3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor

Bioorg Med Chem. 2003 Feb 20;11(4):539-49. doi: 10.1016/s0968-0896(02)00451-0.

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)=17-23nM) 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cannabinoids / chemistry
  • Cannabinoids / pharmacology*
  • Cyclohexanols / pharmacology
  • Dronabinol / metabolism
  • Hydrogen Bonding
  • Indicators and Reagents
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Receptors, Cannabinoid
  • Receptors, Drug / chemistry
  • Receptors, Drug / drug effects*
  • Spectrophotometry, Infrared
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Cannabinoids
  • Cyclohexanols
  • Indicators and Reagents
  • Indoles
  • Ligands
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol