Abstract
Abstract Background and Aim By using an in vivo phenotypic screening assay in zebrafish, we identified Convolamine, a tropane alkaloid from Convulvus plauricalis , as a positive modulator of the sigma‐1 receptor (S1R). The wfs1ab KO zebrafish larva, a model of Wolfram syndrome, exhibits an increased visual‐motor response due to a mutation in Wolframin, a protein involved in endoplasmic reticulum‐mitochondria communication. We previously reported that ligand activating S1R, restored the cellular and behavioral deficits in patient fibroblasts and zebrafish and mouse models. Experimental Procedures We screened a library of 108 repurposing and natural compounds on zebrafish motor response. Key Results One hit, the tropane alkaloid Convolamine, restored normal mobility in wfs1ab KO larvae without affecting wfs1ab WT controls. They did not bind to the S1R agonist/antagonist binding site nor dissociated S1R from BiP, an S1R activity assay in vitro, but behaved as a positive modulator by shifting the IC 50 value of the reference agonist PRE‐084 to lower values. Convolamine restored learning in Wfs1 ∆Exon8 , Dizocilpine‐treated, and Aβ 25‐35 ‐treated mice. These effects were observed at low ~1 mg/kg doses, not shared by Convolvine, the desmethyl metabolite, and blocked by an S1R antagonist. Conclusion and Implications Convolamine therefore acts as an S1R positive modulator and this pharmacological action is relevant to the traditional use of Shankhpushpi in memory and cognitive protection.