Development of a novel drug targeting TRPC3/C6 channels

Abstract

A group of TRPCs, TRPC3, TRPC6, and TRPC7, form Ca²⁺-permeable channels directly activated by diacylglycerol (DAG) and play important roles in regulating neuronal survival and dendritic growth, cardiovascular fibrosis in vitro and in vivo  through regulation of Ca²⁺signaling. Various compounds targeting these TRPC channels have been developed for the treatment of serious diseases such as sudden pulmonary fibrosis and chronic nephropathy. However, none of these compounds have yet reached clinical application, and therefore development of new TRPC3/C6/C7 inhibitors has been much-needed. Here, we have developed a piperazine derivative targeting TRPC3/C6 channels. This compound suppressed receptor-activated Ca²⁺influx in a dose-dependent manner in human embryonic kidney cells 293 expressed with human TRPC3 or TRPC6 (TRPC3, IC₅₀ = 0.086: TRPC6, IC₅₀ = 0.034µM). This drug showed no significant inhibitory or stimulatory effect on other TRPs including TRPC7. Interestingly, during isolation of human TRPC7, we obtained a new splice variant of human TRPC7; we are in the process to characterize biophysical and pharmacological properties of the variant that has a deletion in one of the functionally critical domains.