HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor
L Hanuš, A Breuer, S Tchilibon… - Proceedings of the …, 1999 - National Acad Sciences
L Hanuš, A Breuer, S Tchilibon, S Shiloah, D Goldenberg, M Horowitz, RG Pertwee…
Proceedings of the National Academy of Sciences, 1999•National Acad SciencesTwo 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 …
(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 …
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 (Ki > 10 μM), but does so efficiently to CB2 (Ki = 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.
National Acad Sciences