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Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists

Standard

Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists. / Moreau, Christelle; Kirchberger, Tanja; Swarbrick, Joanna M; Bartlett, Stephen J; Fliegert, Ralf; Yorgan, Timur; Bauche, Andreas; Harneit, Angelika; Guse, Andreas H; Potter, Barry V L.

In: J MED CHEM, Vol. 56, No. 24, 27.12.2013, p. 10079-102.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Moreau, C, Kirchberger, T, Swarbrick, JM, Bartlett, SJ, Fliegert, R, Yorgan, T, Bauche, A, Harneit, A, Guse, AH & Potter, BVL 2013, 'Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists', J MED CHEM, vol. 56, no. 24, pp. 10079-102. https://doi.org/10.1021/jm401497a

APA

Moreau, C., Kirchberger, T., Swarbrick, J. M., Bartlett, S. J., Fliegert, R., Yorgan, T., Bauche, A., Harneit, A., Guse, A. H., & Potter, B. V. L. (2013). Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists. J MED CHEM, 56(24), 10079-102. https://doi.org/10.1021/jm401497a

Vancouver

Moreau C, Kirchberger T, Swarbrick JM, Bartlett SJ, Fliegert R, Yorgan T et al. Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists. J MED CHEM. 2013 Dec 27;56(24):10079-102. https://doi.org/10.1021/jm401497a

Bibtex

@article{ebe62ce34c9240d8a0c5ea2f202cb1d6,
title = "Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists",
abstract = "Adenosine 5'-diphosphoribose (ADPR) activates TRPM2, a Ca(2+), Na(+), and K(+) permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2'-deoxy-ADPR (86, IC50 = 3 μM), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca(2+) signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.",
keywords = "Adenosine Diphosphate Ribose, Dose-Response Relationship, Drug, Drug Design, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship, TRPM Cation Channels",
author = "Christelle Moreau and Tanja Kirchberger and Swarbrick, {Joanna M} and Bartlett, {Stephen J} and Ralf Fliegert and Timur Yorgan and Andreas Bauche and Angelika Harneit and Guse, {Andreas H} and Potter, {Barry V L}",
year = "2013",
month = dec,
day = "27",
doi = "10.1021/jm401497a",
language = "English",
volume = "56",
pages = "10079--102",
journal = "J MED CHEM",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "24",

}

RIS

TY - JOUR

T1 - Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists

AU - Moreau, Christelle

AU - Kirchberger, Tanja

AU - Swarbrick, Joanna M

AU - Bartlett, Stephen J

AU - Fliegert, Ralf

AU - Yorgan, Timur

AU - Bauche, Andreas

AU - Harneit, Angelika

AU - Guse, Andreas H

AU - Potter, Barry V L

PY - 2013/12/27

Y1 - 2013/12/27

N2 - Adenosine 5'-diphosphoribose (ADPR) activates TRPM2, a Ca(2+), Na(+), and K(+) permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2'-deoxy-ADPR (86, IC50 = 3 μM), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca(2+) signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.

AB - Adenosine 5'-diphosphoribose (ADPR) activates TRPM2, a Ca(2+), Na(+), and K(+) permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2'-deoxy-ADPR (86, IC50 = 3 μM), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca(2+) signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.

KW - Adenosine Diphosphate Ribose

KW - Dose-Response Relationship, Drug

KW - Drug Design

KW - Humans

KW - Models, Molecular

KW - Molecular Structure

KW - Structure-Activity Relationship

KW - TRPM Cation Channels

U2 - 10.1021/jm401497a

DO - 10.1021/jm401497a

M3 - SCORING: Journal article

C2 - 24304219

VL - 56

SP - 10079

EP - 10102

JO - J MED CHEM

JF - J MED CHEM

SN - 0022-2623

IS - 24

ER -