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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Christelle
authors.initials: C
authors.lastname: Moreau
authors.forename: Tanja
authors.initials: T
authors.lastname: Kirchberger
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Swarbrick
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Bartlett
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.forename: Timur
authors.initials: T
authors.lastname: Yorgan
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauche
authors.forename: Angelika
authors.initials: A
authors.lastname: Harneit
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D000246:Adenosine Diphosphate Ribose