New resorcinol-anandamide "hybrids" as potent cannabinoid receptor ligands endowed with antinociceptive activity in vivo

J Med Chem. 2009 Apr 23;52(8):2506-14. doi: 10.1021/jm8016255.

Abstract

Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB(2) receptor (K(i)(CB(1)) = 1 muM, K(i)(CB(2)) = 35 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Arachidonic Acids / chemical synthesis*
  • Arachidonic Acids / chemistry
  • Arachidonic Acids / pharmacology
  • COS Cells
  • Cannabinoid Receptor Agonists*
  • Cannabinoid Receptor Antagonists*
  • Chlorocebus aethiops
  • Drug Partial Agonism
  • Endocannabinoids
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Pain Measurement
  • Phenols / chemical synthesis*
  • Phenols / chemistry
  • Phenols / pharmacology
  • Polyunsaturated Alkamides / chemical synthesis*
  • Polyunsaturated Alkamides / chemistry
  • Polyunsaturated Alkamides / pharmacology
  • Radioligand Assay
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / metabolism
  • Resorcinols / chemical synthesis*
  • Resorcinols / chemistry
  • Resorcinols / pharmacology
  • Stereotyped Behavior / drug effects
  • Structure-Activity Relationship

Substances

  • 8-(5-(2-Methyloctan-2-yl)phenoxy)octanoic acid cyclopropylamide
  • Analgesics
  • Arachidonic Acids
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Endocannabinoids
  • Ligands
  • Phenols
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Resorcinols
  • anandamide
  • resorcinol