title: Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2.
abstract: P2 membrane receptors for nucleotides represent significant targets for experimental pharmacology and drug research. In earlier publications, we have shown that Reactive Blue 2 (RB 2), one of the most widely used P2-receptor antagonists, displays only moderate affinity and does not discriminate between native P2X- and P2Y-receptor subtypes. In the present study we have pharmacologically evaluated a series of 15 synthesized and re-evaluated four commercially obtained and chromatographically purified RB 2 type anthraquinone derivatives on contractions of the rat vas deferens (RVD) elicited by alpha,beta-methylene ATP (alpha,beta-meATP), mediated by P2X1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic pi-electron systems, hydrogen bonds with nitrogen as donor and acceptor atoms, and, particularly, position, conformational distance and number of anionic sulfonate groups are of great importance for the blockade of the two native P2-receptor subtypes. We have also identified novel, for the most part reversible antagonists that bind with higher affinity and improved subtype selectivity in comparison to RB 2. In particular, 1-amino-4-{4-[4-chloro-6-(2-sulfonatophenylamino)-[1,3,5]triazine-2-ylamino]-2-sulfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y1-like-receptors of the GPTC reported so far (IC50=4.6 nM). It is significantly less potent as reversible antagonist at the P2X1-receptors of the RVD (IC50=2.8 microM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations.
authors.affiliation: Institut für Pharmazeutische Wissenschaften Albertstrasse 25, D-79104 Freiburg i.Br., Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glänzel
authors.forename: Ralph
authors.initials: R
authors.lastname: Bültmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Starke
authors.forename: August W
authors.initials: AW
authors.lastname: Frahm
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000873:Anthracenes; C509172:MG 50-3-1; D058919:Purinergic P2 Receptor Antagonists; D014227:Triazines; C012842:Cibacron Blue F 3GA; D002217:Carbachol