HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.

  • Hanus L
  • Breuer A
  • Tchilibon S
 et al. 
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Abstract

Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)-transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

Author-supplied keywords

  • Analgesics
  • Analgesics: pharmacology
  • Animals
  • Arachidonic Acid
  • Arachidonic Acid: pharmacology
  • Blood Pressure
  • Blood Pressure: drug effects
  • Bornanes
  • Bornanes: pharmacology
  • Cannabinoids
  • Cannabinoids: metabolism
  • Cannabinoids: pharmacology
  • Cyclic AMP
  • Cyclic AMP: biosynthesis
  • Female
  • Mice
  • Piperidines
  • Piperidines: pharmacology
  • Pyrazoles
  • Pyrazoles: pharmacology
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Receptors, Drug: agonists
  • Receptors, Drug: physiology
  • Structure-Activity Relationship

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Authors

  • L Hanus

  • A Breuer

  • S Tchilibon

  • S Shiloah

  • D Goldenberg

  • M Horowitz

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