Add time:07/11/2019         Source:sciencedirect.com

Two subtypes of cannabinoid receptors are currently recognized, CB1, found in brain and neuronal cells, and CB2, found in spleen and immune cells. We have characterized 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid phenylamide (CP-272871) as a novel aryl pyrazole antagonist for the CB1 receptor. CP-272871 competed for binding of the cannabinoid agonist 3H-labeled (−)-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol ([3H]CP-55940) at the CB1 receptor in rat brain membranes with a Kd value 20-fold greater than that of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). CP-272871 also competed for binding with the aminoalkylindole agonist 3H-labeled (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl)methanone ([3H]WIN-55212–2), as well as the aryl pyrazole antagonist [3H]SR141716A. Inverse agonist as well as antagonist properties were observed for both SR141716A and CP-272871 in signal transduction assays in biological preparations in which the CB1 receptor is endogenously expressed. SR141716A augmented secretin-stimulated cyclic AMP (cAMP) accumulation in intact N18TG2 neuroblastoma cells, and this response was reversed by the agonist desacetyllevonantradol. CP-272871 antagonized desacetyllevonantradol-mediated inhibition of adenylyl cyclase in N18TG2 membranes, and increased adenylyl cyclase activity in the absence of agonist. SR141716A and CP-272871 antagonized desacetyllevonantradol-stimulated 35S-labeled guanosine-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) binding to brain membrane G-proteins, and decreased basal [35S]GTPγS binding to G-proteins. K+ enhanced CP-272871 and SR141716A inverse agonist activity compared with Na+ or NMDG+ in the assay. These results demonstrated that the aryl pyrazoles SR141716A and CP-272871 behave as antagonists and as inverse agonists in G-protein-mediated signal transduction in preparations of endogenously expressed CB1 receptors.

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