Convolamine, a tropane alkaloid extracted from Convolvulus plauricalis, is a potent sigma‐1 receptor‐positive modulator with cognitive and neuroprotective properties

Abstract

Background and AimBy 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 wfs1abKO 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 ProceduresWe screened a library of 108 repurposing and natural compounds on zebrafish motor response.Key ResultsOne hit, the tropane alkaloid Convolamine, restored normal mobility in wfs1abKO larvae without affecting wfs1abWT 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 IC50 value of the reference agonist PRE‐084 to lower values. Convolamine restored learning in Wfs1∆Exon8, Dizocilpine‐treated, and Aβ25‐35‐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 ImplicationsConvolamine therefore acts as an S1R positive modulator and this pharmacological action is relevant to the traditional use of Shankhpushpi in memory and cognitive protection.

Identification of Psychoplastogenic Tropanes Lacking Muscarinic Activity

“…Here, we report the identification of several tropanes from various structural classes capable of significantly increasing neurite outgrowth while exhibiting greatly reduced activity at all MRs. Interestingly, these compounds appear to promote plasticity without directly activating the 5-HT2AR or 5-HT2CR. Tropane containing molecules are known to modulate several receptors that are implicated in various forms of plasticity including sigma-1 receptors, − dopamine receptors, − monoamine transporters, , adrenergic receptors, , opioid receptors, − and nicotinic acetylcholine receptors. , However, a common target shared by all psychoplastogenic tropanes is not obvious. Consequently, it is unclear if psychoplastogenic tropanes share a common target, or if their effects are the result of polypharmacological mechanisms.…”