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Aims We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. Main methods Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. Key findings The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. Significance Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke. Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect. Surprisingly the double knockout animals had improved outcome. Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results. [ABSTRACT FROM AUTHOR]

Abstract: The relevance of CB2R-mediated therapeutic effects is well-known for the treatment of inflammatory and neuropathic pain and neurodegenerative disorders. In our search for new cannabinoid receptor modulators, we report the optimization of a series of 1,2-dihydro-2-oxopyridine-3-carboxamide derivatives as CB2R ligands. In particular, N-cycloheptyl-5-(4-methoxyphenyl)-1-(4-fluorobenzyl)-pyridin-2(1H)-on-3-carboxamide (17) showed high CB2R affinity (K i = 1.0 nM), accompanied by interesting K i(CB1R)/K i(CB2R) selectivity ratio (SI = 43.4). Compound 17 was also identified as a potent CB2R neutral antagonist/weak partial inverse agonist. Finally we found that the functionality activity of the series of 1,2-dihydro-2-oxopyridine is controlled by the presence of a substituent in position 5 of the heterocyclic nucleus. In fact when the hydrogen atom in position 5 of the unsubstituted compound 1 was replaced with a phenyl group (compound 18) the CB2R activity was shifted from agonism to inverse agonism whereas the introduction in the same position of p-methoxyphenyl group lead to compound 17 which showed a behavior as CB2R neutral antagonist/weak partial inverse agonist. [Copyright &y& Elsevier]

Abstract: CB2 receptor ligands are becoming increasingly attractive drugs due to the potential role of this receptor in several physiopathological processes. Using our previously described series of 1,8-naphthyridin-2(1H)-on-3-carboxamides as a lead class, several nitrogen heterocyclic derivatives, characterized by different central cores, were synthesized and tested for their affinity toward the human CB1 and CB2 cannabinoid receptors. The obtained results suggest that the new series of quinolin-2(1H)-on-3-carboxamides, 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides and 1,2-dihydro-2-oxopyridine-3-carboxamides represent novel scaffolds very suitable for the development of promising CB2 ligands. Furthermore, the newly synthesized CB2 ligands inhibit proliferation of several cancer cell lines. In particular, it was demonstrated that in DU-145 cell line these ligands exert a CB2-mediated anti-proliferative action and decrease the CB2 receptor expression levels. [Copyright &y& Elsevier]