title: Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
abstract: Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Ullmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Meis
authors.forename: Darunee
authors.initials: D
authors.lastname: Hongwiset
authors.forename: Claudia
authors.initials: C
authors.lastname: Marzian
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.forename: Peter
authors.initials: P
authors.lastname: Nickel
authors.forename: Didier
authors.initials: D
authors.lastname: Communi
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Christian
authors.initials: C
authors.lastname: Wolf
authors.forename: Ralf
authors.initials: R
authors.lastname: Hausmann
authors.forename: Günther
authors.initials: G
authors.lastname: Schmalzing
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013498:Suramin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C526891:NF157 compound; C109734:P2RY11 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013498:Suramin; D002118:Calcium