AM630 behaves as a protean ligand at the human cannabinoid CB2 receptor

作者：Bolognini Daniele; Cascio Maria Grazia; Parolaro Daniela; Pertwee Roger G^*

来源：British Journal of Pharmacology, 2012, 165(8): 2561-2574.

DOI：10.1111/j.1476-5381.2011.01503.x

• cannabinoid CB2 receptor
• AM630
• SR144528
• CP55940
• 9-tetrahydrocannabivarin
• R-(+)-WIN55212
• inverse agonism
• neutral antagonism
• two-state model of agonism and inverse agonism
• protean ligand

BACKGROUND AND PURPOSE %26lt;br%26gt;We have investigated how pre-incubating hCB(2) CHO cells with the CB2 receptor antagonists/inverse agonists, AM630 and SR144528, affects how these and other ligands target hCB(2) receptors in these cells or their membranes. %26lt;br%26gt;EXPERIMENTAL APPROACH %26lt;br%26gt;We tested the ability of AM630, SR144528 and of the CB1/CB2 receptor agonists, CP55940 and R-(+)-WIN55212, to modulate forskolin-stimulated cAMP production in hCB(2) CHO cells or [S-35]-GTP gamma S binding to membranes prepared from these cells, or to displace [H-3]-CP55940 from whole cells and membranes. Assays were also performed with the CB2 receptor partial agonist, Delta(9)-tetrahydrocannabivarin. Some cells were pre-incubated with AM630 or SR144528 and then washed extensively. KEY %26lt;br%26gt;RESULTS %26lt;br%26gt;AM630 behaved as a low-potency neutral competitive antagonist in AM630-pre-incubated cells, a low-potency agonist in SR144528-pre-incubated cells, and a much higher-potency inverse agonist/antagonist in vehicle-pre-incubated cells. AM630 pre-incubation (i) reduced the inverse efficacy of SR144528 without abolishing it; (ii) increased the efficacy of D9-tetrahydrocannabivarin; and (iii) did not affect the potency with which AM630 displaced [H-3]-CP55940 from whole cells or its inverse agonist potency and efficacy in the [S-35]-GTPgS membrane assay. %26lt;br%26gt;CONCLUSIONS AND IMPLICATIONS %26lt;br%26gt;These results suggest that AM630 is a protean ligand that can target a constitutively active form of the hCB(2) receptor (R*) with low affinity to produce agonism or neutral antagonism and a constitutively inactive form of this receptor (R) with much higher affinity to produce inverse agonism, and that the constitutive activity of whole cells is decreased less by pre-incubation with AM630 than with the higher-efficacy inverse agonist, SR144528.

• 出版日期2012-4
• 单位河北医科大学