Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

Abstract

Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5'-diphosphoribose (ADPR) analogues were synthesized and their activities and selectivity were evaluated. Whole-cell patch clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a were identified as TRPM2 inhibitors with IC₅₀ of 5.7 μM and 5.4 μM, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure-activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.

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A series of adenosine 5'-diphosphoribose (ADPR) analogues were synthesized for discovering novel and selective TRPM2 inhibitors. Two compounds, 7i and 8a were identified as TRPM2 inhibitors with IC₅₀ of 5.7 μM, respectively, selective against TRPM7, TRPM8, TRPV1 and TRPV3. These two novel and TRP-subtype selective TRPM2 inhibitors can be used as tool for further investigation of the channel pharmacology.

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