Birnkammer, Tobias and Spickenreither, Anja and Brunskole, Irena and Lopuch, Miroslaw and Kagermeier, Nicole and Bernhardt, Günther and Dove, Stefan and Seifert, Roland and Elz, Sigurd and Buschauer, Armin (2012) The bivalent ligand approach leads to highly potent and selective acylguanidine-type histamine H2 receptor agonists. Journal of Medicinal Chemistry 55 (3), pp. 1147-1160.
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Bivalent histamine H2 receptor (H2R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)- or 3-(1,2,4-triazol-5-yl)-propylguanidine moieties by NG-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [35S]GTPγS binding assays at guinea pig (gp) and human (h) H2R-GsαS fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H1, H3 and H4 receptors. The bivalent ligands are H2R partial or full agonists, up to two orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH2R. In contrast to their imidazole analogs, the aminothiazoles are highly selective for H2R vs. other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH2 groups) to simultaneously occupy two orthosteric binding sites in H2R dimers are nearly inactive, whereas highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H2R dimers. The high agonistic potency may rather result from interaction with an accessory binding site at the same receptor protomer.
|Date:||5 January 2012|
|Additional information (public):||Online veröffentlicht als "just accepted manuscript" am 5. Januar 2012|
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
|Projects:||GRK 760, Graduiertenkolleg Medizinische Chemie|
|Research groups and research centres:||Not selected|
|Keywords:||Acylguanidine, bivalent ligand, GTPase assay, histamine H2 receptor, receptor selectivity|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
500 Science > 570 Life sciences
600 Technology > 615 Pharmacy
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Owner:||Prof. Armin Buschauer|
|Deposited On:||09 Jan 2012 12:23|
|Last Modified:||07 Jul 2012 07:38|