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

Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, pre sent outside the CNS, in peripheral organs. There is evidence for the prese nce of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannab inoid 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 produc tion in CB2-transfected cells, but does so much less in CB1-transfected cel ls. HU-308 shows no activity in mite in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-typ e activity in the CNS mediated by CB1. However, HU-308 reduces blood pressu re, blocks defecation, and elicits anti-inflammatory and peripheral analges ic activity. The hypotension, the inhibition of defecation, the anti-inflam matory and peripheral analgesic effects produced by HU-308, are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 ant agonist SR-141716A. These results demonstrate the feasibility of discoverin g novel nonpsychotropic cannabinoids that may lead to new therapies for hyp ertension, inflammation, and pain.