Abstract
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 mu M), 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 mite 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.
Original language | English |
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Pages (from-to) | 14228-14233 |
Number of pages | 6 |
Journal | PNAS |
Volume | 96 |
Issue number | 25 |
DOIs | |
Publication status | Published - 7 Dec 1999 |
Keywords
- endogenous cannabinoids
- induced hypotension
- brain constituent
- anandamide
- identification
- pharmacology
- motility
- ligands
- analogs
- binds