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

TLDR

Two cannabinoid receptors, CB1 in the CNS and CB2 in peripheral tissues, have been identified, with evidence of CB2‑like receptors in peripheral nerve terminals. The study reports the synthesis of a CB2‑specific agonist, HU‑308. HU‑308 was characterized by binding assays showing high affinity for CB2 (Ki ≈ 23 nM) and negligible CB1 affinity, and by functional assays demonstrating inhibition of forskolin‑stimulated cAMP in CB2‑transfected cells. HU‑308 exhibits peripheral effects—hypotension, anti‑inflammatory, analgesic, and anti‑defecation actions—without CNS activity, and these effects are blocked by the CB2 antagonist SR‑144528 but not by the CB1 antagonist SR‑141716A, indicating a non‑psychotropic therapeutic potential.

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.