HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

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 μM), 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.