| Item type: | Article | ||||||
|---|---|---|---|---|---|---|---|
| Journal or Publication Title: | Journal of Medicinal Chemistry | ||||||
| Publisher: | AMER CHEMICAL SOC | ||||||
| Place of Publication: | WASHINGTON | ||||||
| Volume: | 55 | ||||||
| Number of Issue or Book Chapter: | 3 | ||||||
| Page Range: | pp. 1147-1160 | ||||||
| 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 (Historical): | GRK 760, Graduiertenkolleg Medizinische Chemie | ||||||
| Interdisciplinary Subject Network: | Not selected | ||||||
| Identification Number: |
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| Related URLs: |
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| 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; | ||||||
| Dewey Decimal Classification: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy 600 Technology > 615 Pharmacy | ||||||
| Status: | Published | ||||||
| Refereed: | Yes, this version has been refereed | ||||||
| Created at the University of Regensburg: | Yes | ||||||
| Item ID: | 21744 |
Web of ScienceAbstract
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 ...
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.
Metadata last modified: 29 Sep 2021 07:38
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