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, 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.