HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.
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 microM), 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.
Hanus
L
L
Department of Medicinal Chemistry, Medical Faculty, Hebrew University, Jerusalem 91120, Israel.
Breuer
A
A
Tchilibon
S
S
Shiloah
S
S
Goldenberg
D
D
Horowitz
M
M
Pertwee
R G
RG
Ross
R A
RA
Mechoulam
R
R
Fride
E
E
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000502:physiology; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D000700:Analgesics; D001892:Camphanes; D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; D016718:Arachidonic Acid; C402416:HU 308; D000242:Cyclic AMP; D000077285:Rimonabant