RT Journal Article
SR Electronic
T1 SKF83959 is a Potent Allosteric Modulator of Sigma-1 Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.083840
DO 10.1124/mol.112.083840
A1 Lin Guo
A1 Jianghao Zhao
A1 Guozhang Jin
A1 Bin Zhao
A1 Guanghui Wang
A1 Ao Zhang
A1 Xuechu Zhen
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/01/07/mol.112.083840.abstract
AB SKF83959, an atypical dopamine receptor-1(D1 receptor) agonist, has showed many D1 receptor-independent effects, such as neuroprotection, blockade of Na+ channel, and promotion of spontaneous glutamate release, which somehow resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF835959 dramatically promoted the binding of 3H(+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues, but produced no effect on 3H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 and SKF38393, also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on 3H-1,3-di(2-tolyl)-guanidine(3H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D1 receptor-independent effect of the drug.