Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist

Life Sci. 1995;56(23-24):1941-7. doi: 10.1016/0024-3205(95)00174-5.

Abstract

SR141716A is a selective, potent and orally active antagonist of the brain cannabinoid receptor with a long duration of action. This compound shows high affinity for the central cannabinoid receptor (Ki = 2 nM), displays low affinity for the peripheral cannabinoid receptor (Ki > 1000 nM). In vitro, SR141716A antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and dopamine-stimulated adenylyl cyclase activities in rat brain membranes. After oral administration SR141716A totally inhibited the ex vivo [3H]-CP55,940 binding to cerebral membranes with a ED50 value of 3.5 mg/kg. Furthermore SR141716A antagonizes the classical pharmacological responses elicited by cannabinoid receptor agonists. In addition, SR141716A reverses the inhibitory effect of WIN55212-2 on isoniazid-induced elevation of cGMP in rat cerebellum. This compound will provide a powerful tool for studying the in vivo functions of the anandamide/cannabinoid system.

MeSH terms

  • Animals
  • Benzoxazines
  • Brain / drug effects*
  • Brain / metabolism
  • CHO Cells
  • Cannabinoids / metabolism
  • Cricetinae
  • In Vitro Techniques
  • Male
  • Mice
  • Morpholines / antagonists & inhibitors
  • Morpholines / pharmacology
  • Naphthalenes / antagonists & inhibitors
  • Naphthalenes / pharmacology
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors*
  • Receptors, Drug / metabolism
  • Rimonabant

Substances

  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Win 55212-2
  • Rimonabant