The regulator of G-protein signaling (RGS) proteins are negative regulators of the G-protein coupled receptors signaling pathways. CCG 50014 is a potent, irreversible small molecule inhibitor of RGS4 with an IC50 value of 30nM. It also inhibits other RGS proteins, including RGS8, 16, and 19 with IC50 values of 11, 3.5, and 0.12μM, respectively. CCG 50014 at 10μM inhibited the GTPase accelerating activity of RGS4 and RGS8 on Gα0. Compared to vehicle-treated protein, wild-type RGS8 treated with 100μM CCG 50014 was 14-fold less potent at competing for Gα binding. When treated with CCG 50014 at 20μM, the binding of 107C RGS8 to Gα was inhibited by ~20% and the binding of 160C RGS8 to Gα was inhibited by ~50%. CCG 50014 at 100μM inhibited Gα0-dependent membrane translocation of GFP-RGS4 in living HEK293T cells.[3] The intrathecal administration with CCG50014 (10, 30, or 100nmol) dose-dependently attenuated nociceptive responses and enhanced opioid-mediated analgesic effects in mice injected with formalin.[4]
作用机制
CCG 50014 may inhibit RGS protein through sulfhydryl modification. It covalently binds to RGS protein, forming an adduct on two cysteine residues located in an allosteric regulatory site.[3]
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