A Selective TRPC3 Antagonist Rescues Neuronal Loss and Facilitates Spatial Learning and Memory in Alzheimer's Model

Abstract

ID 14268 Poster Board 314Aberrant calcium signaling has intimate associations with multiple diseases. Upregulation of transient receptor potential canonical 3 (TRPC3), which is an ion channel that essentially mediates calcium influx, drives the progression of neurodegenerative diseases. We previously designed JW-65, a selective TRPC3 inhibitor with a favorable safety profile and good metabolic stability. However, JW-65 has moderate potency (IC 50 = 330 nM) and selectivity for TRPC3 inhibition. Here we report a synthetic JW-65 analog, 60a, with significantly improved potency and selectivity. 60a is a potent TRPC3 inhibitor (IC 50 = 90 nM) with no detectable inhibitory effect on the close homologs TRPC6/7, highlighting 60a as the first truly selective TRPC3 inhibitor. In vitro evaluations of 60a reveal its rescuing abilities on neuronal damage. In vivo studies indicate 60a is a promising candidate for further development as a potential AD therapy with a novel mechanism of action.