Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding

Drug Alcohol Depend. 2000 Aug 1;60(2):133-40. doi: 10.1016/s0376-8716(99)00152-0.

Abstract

The N-1 alkyl side chain of the aminoalkylindole analogues (AAI) has been implicated as one of a three-point interaction with the cannabinoid CB(1) receptor. In this study, the morpholinoethyl of WIN 55,212-2 was replaced with carbon chains of varying lengths ranging from a methyl to heptyl group. Additional groups were added to the naphthoyl and the C2 positions of the molecule. These structural changes revealed that high affinity binding to the CB(1) and CB(2) receptors requires an alkyl chain length of at least three carbons with optimum binding to both receptors occurring with a five carbon side chain. An alkyl chain of 3-6 carbons is sufficient for high affinity binding; however, extension of the chain to a heptyl group results in a dramatic decrease in binding at both receptors. The unique structure of the cannabimimetic indoles provides a useful tool to define the ligand-receptor interaction at both cannabinoid receptors and to refine proposed pharmacophore models.

Publication types

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

MeSH terms

  • Animals
  • Benzoxazines
  • CHO Cells
  • Cannabinoids / chemistry
  • Cannabinoids / metabolism*
  • Cricetinae
  • Dronabinol / chemistry
  • Dronabinol / metabolism*
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism*
  • Morpholines / chemistry
  • Morpholines / metabolism
  • Naphthalenes / chemistry
  • Naphthalenes / metabolism
  • Receptors, Cannabinoid
  • Receptors, Drug / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzoxazines
  • Cannabinoids
  • Indoles
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dronabinol