HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor

L Hanus, A Breuer, S Tchilibon, S Shiloah, D Goldenberg, M Horowitz, R G Pertwee, R A Ross, R Mechoulam, E Fride

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Abstract

Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1 (K-i > 10 mu M), but does so efficiently to CB2 (K-i = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mite in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. 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 CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

Original languageEnglish
Pages (from-to)14228-14233
Number of pages6
JournalPNAS
Volume96
Issue number25
DOIs
Publication statusPublished - 7 Dec 1999

Keywords

  • endogenous cannabinoids
  • induced hypotension
  • brain constituent
  • anandamide
  • identification
  • pharmacology
  • motility
  • ligands
  • analogs
  • binds

Cite this

Hanus, L., Breuer, A., Tchilibon, S., Shiloah, S., Goldenberg, D., Horowitz, M., Pertwee, R. G., Ross, R. A., Mechoulam, R., & Fride, E. (1999). HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. PNAS, 96(25), 14228-14233. https://doi.org/10.1073/pnas.96.25.14228