Inhibitory effects of SR141716A on G-protein activation in rat brain.
Inhibitory effects of SR141716A on G-protein activation in rat brain.
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DOI：
10.1016/s0014-2999(01)00784-1
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发表时间：
2001-03
影响因子：
5
通讯作者：
L. Sim‐Selley;Leah K. Brunk;D. Selley
中科院分区：
文献类型：
--
作者：
L. Sim‐Selley;Leah K. Brunk;D. Selley
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), a cannabinoid CB1receptor antagonist, has inverse agonist effects in cannabinoid CB1receptor-expressing cell lines, brain and peripheral organs. These studies characterized SR141716A-inhibited G-protein activity by measuring [35S]GTPγS binding. Maximal inhibition of basal [35S]GTPγS binding in cerebellar membranes was 50%. The EC50value for inhibition of [35S]GTPγS binding was 4.4 μM, whereas the Kefor inhibition of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2)-stimulated [35S]GTPγS binding was 0.6 nM. [35S]GTPγS autoradiography was used to examine the regional specificity of SR141716A inhibition. SR141716A inhibited basal [35S]GTPγS binding in all regions examined, with inhibition ranging from approximately 20% in caudate-putamen to 40% in hippocampus. These studies demonstrate that SR141716A is a competitive antagonist at nanomolar concentrations, whereas it inhibits basal receptor-mediated G-protein activity at micromolar concentrations. These data suggest that the apparent inverse agonist effect is either not cannabinoid CB1receptor-specific or that SR141716A is binding to different sites on the cannabinoid CB1receptor to produce inverse agonist versus competitive antagonist effects.
