Birnkammer, Tobias and Spickenreither, Anja and Brunskole, Irena and Lopuch, Miroslaw and Kagermeier, Nicole and Bernhardt, Guenther 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 H-2 Receptor Agonists. JOURNAL OF MEDICINAL CHEMISTRY, 55 (3). pp. 1147-1160. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
Bivalent histamine H-2 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 N-G-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [S-35]GTP gamma S binding assays at guinea pig (gp) and human (h) H2R-Gs alpha(s) fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H-1, H-3, and H-4 receptors. The bivalent ligands are H2R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R In contrast to their imidazole analogues, 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 the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H2R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; 2ND EXTRACELLULAR LOOP; G-ACYLATED IMIDAZOLYLPROPYLGUANIDINES; NUCLEOTIDE-BINDING PROTEINS; RESONANCE ENERGY-TRANSFER; IN-VITRO PHARMACOLOGY; H-4 RECEPTOR; SF9 CELLS; GUANOSINE 5-O-(3-THIOTRIPHOSPHATE); CONSTITUTIVE ACTIVITY; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 May 2020 11:21 |
| Last Modified: | 19 May 2020 11:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19236 |
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