Received: JAccepted: DecemPublished: January 31, 2018Ĭopyright: © 2018 Just et al. Obukhov, Indiana University School of Medicine, UNITED STATES (2018) Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.Ĭitation: Just S, Chenard BL, Ceci A, Strassmaier T, Chong JA, Blair NT, et al. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC 50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM.
Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity.