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Selective inhibition of TRPM 2 channel by two novel synthesized ADPR analogues
Author(s) -
Luo Xiao,
Li Meng,
Zhan Kaiyu,
Yang Wei,
Zhang Lihe,
Wang KeWei,
Yu Peilin,
Zhang Liangren
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13119
Subject(s) - transient receptor potential channel , trpv , chemistry , biochemistry , microbiology and biotechnology , receptor , biology , trpv1
Transient receptor potential melastatin‐2 ( TRPM 2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM 2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM 2 inhibitors, a series of adenosine 5′‐diphosphoribose 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 TRPM 2 inhibitors with IC 50 of 5.7 and 5.4 μ m , respectively. Both 7i and 8a inhibited TRPM 2 current without affecting TRPM 7, TRPM 8, TRPV 1 and TRPV 3. These two TRPM 2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM 2 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.