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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

512 Scopus citations

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 μM), 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 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 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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number25
DOIs
StatePublished - 7 Dec 1999

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