Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists
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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, Jahrgang 56, Nr. 24, 27.12.2013, S. 10079-102.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -