In vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (TRPV1) inhibitor GRTE16523.

In vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (TRPV1) inhibitor GRTE16523. Eur J Pharmacol. 2020 Jan 16;:172934 Authors: Damann N, Bahrenberg G, Stockhausen H, Habermann CJ, Lesch B, Frank-Foltyn R, Lee J, Ann J, Christoph T Abstract The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia turned out as major side effects of TRPV1 antagonists, preventing successful development of such molecules as analgesics. In vitro studies demonstrated that the TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature dependent gating is suggested to constitute the molecular basis for its role in heat sensation and body temperature regulation. Drug discovery scientists since many years seek to obtain "thermoneutral" TRPV1 inhibitors, blocking the channels sensitivity for painful stimuli while keeping its temperature mode of activation unaffected. Aiming for a screening rational for the identification of thermoneutral TRPV1 antagonists, we broadly characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. In vitro, GRT12360V demonstrated pan-modality inhibition on human, cynomolgus and rodent TRPV1, whereas GRTE16523 selectively bypassed the channels temperatur...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research