Identification Of Novel Sigma-1 Receptor Ligands And Preliminary Exploration Of Their Antidepressant Activity

Objective:Sigma-1 receptor is a therapeutic target for neuropsychiatric disorders such as depression.In the early stage of this study,several new compounds having high affinity with Sigma-1 receptor were discovered by computer-aided drug design methods such as computer docking.On this basis,we screened and confirmed the specific effects of these compounds on Sigma-1 receptor from the perspective of biological function.In addition,the antidepressant effect of the candidate compounds in the animal model was discussed.It provides a powerful experimental basis for discovering new Sigma-1 receptor ligands.Methods:Using competitive binding experiments with ³H?+?-pentazocine?highly selective Sigma-1 receptor agonist?and ³H-DTG?highly selective Sigma-2 receptor agonist?,we calculated the half-inhibitory concentration IC₅₀ and suppression constant K_ito screen candidate compounds with high affinity and selectivity to Sigma-1 receptor for the following functional verification of biological activity.In the HT-22 mouse hippocampal neuronal cell line,the binding of Sigma-1 receptor to Bip protein was detected by co-immunoprecipitation and the phosphorylation level of GSK-3?was detected by immunoblotting to analyze the biological effects on Sigma-1 receptor of candidate compounds.The antidepressant effects of candidate compounds were preliminarily explored by tail suspension test,forced swimming test in mice LPS-induced acute depression model.Results:Compound D491-1682(IC₅₀:26.42±0.37 n M;K_i:11.87±3.82)and compound K788-7608(IC₅₀:34.12±2.01 n M;K_i:15.82±6.48)have high affinity and selectivity to Sigma-1 receptor.In vitro study confirmed that both D491-1682 and K788-7608 can induce the dissociation of Sigma-1 receptor from Bip protein,and both compounds promoted the phosphorylation of GSK-3?.In vivo study showed that both D491-1682 and K788-7608 significantly shortened the immobility time of tail suspension test and forced swimming test in LPS-induced mice with depression-like symptoms.And the antidepressant effect was blocked by BD1047,a specific Sigma-1 receptor antagonist.Conclusion:Compound D491-1682 and compound K788-7608 have high affinity with Sigma-1 receptor,which are novel selective Sigma-1 receptor agonists.Both compounds exerted antidepressant effects in LPS-induced acute depression model.