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Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

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 targ...

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Autores principales: Luo, Xiao, Li, Meng, Zhan, Kaiyu, Yang, Wei, Zhang, Lihe, Wang, KeWei, Yu, Peilin, Zhang, Liangren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813235/
https://www.ncbi.nlm.nih.gov/pubmed/29034580
http://dx.doi.org/10.1111/cbdd.13119
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author Luo, Xiao
Li, Meng
Zhan, Kaiyu
Yang, Wei
Zhang, Lihe
Wang, KeWei
Yu, Peilin
Zhang, Liangren
author_facet Luo, Xiao
Li, Meng
Zhan, Kaiyu
Yang, Wei
Zhang, Lihe
Wang, KeWei
Yu, Peilin
Zhang, Liangren
author_sort Luo, Xiao
collection PubMed
description 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 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 IC (50) of 5.7 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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spelling pubmed-58132352018-02-21 Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues Luo, Xiao Li, Meng Zhan, Kaiyu Yang, Wei Zhang, Lihe Wang, KeWei Yu, Peilin Zhang, Liangren Chem Biol Drug Des Research Articles 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 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 IC (50) of 5.7 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. John Wiley and Sons Inc. 2017-11-15 2018-02 /pmc/articles/PMC5813235/ /pubmed/29034580 http://dx.doi.org/10.1111/cbdd.13119 Text en © 2017 The Authors. Chemical Biology & Drug Design Published by John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Luo, Xiao
Li, Meng
Zhan, Kaiyu
Yang, Wei
Zhang, Lihe
Wang, KeWei
Yu, Peilin
Zhang, Liangren
Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title_full Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title_fullStr Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title_full_unstemmed Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title_short Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
title_sort selective inhibition of trpm2 channel by two novel synthesized adpr analogues
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813235/
https://www.ncbi.nlm.nih.gov/pubmed/29034580
http://dx.doi.org/10.1111/cbdd.13119
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