| Dokumentenart: | Artikel | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | ChemMedChem | ||||||||||
| Verlag: | WILEY-BLACKWELL | ||||||||||
| Ort der Veröffentlichung: | MALDEN | ||||||||||
| Band: | 4 | ||||||||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 2 | ||||||||||
| Seitenbereich: | S. 232-240 | ||||||||||
| Datum: | 13 Februar 2009 | ||||||||||
| Zusätzliche Informationen (Öffentlich): | Online publiziert am 15. Dezember 2008 | ||||||||||
| Institutionen: | Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische / Medizinische Chemie II (Prof. Buschauer) Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmakologie und Toxikologie (Prof. Schlossmann, ehemals Prof. Seifert) Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmakologie und Toxikologie (Prof. Schlossmann, ehemals Prof. Seifert) | ||||||||||
| Sonstige Projekte: | GRK 760, Graduiertenkolleg Medizinische Chemie | ||||||||||
| Identifikationsnummer: |
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| Verwandte URLs: |
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| Stichwörter / Keywords: | RECEPTOR; H-1-RECEPTOR; PHARMACOLOGY; HISTAMINE-H2-RECEPTOR; GUANIDINES; AMTHAMINE; LIGANDS; MODELS; acylguanidines; aminothiazoles; GTPase; medicinal chemistry; receptors; structure-activity relationships | ||||||||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 615 Pharmazie 500 Naturwissenschaften und Mathematik > 540 Chemie | ||||||||||
| Status: | Veröffentlicht | ||||||||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||||||||
| An der Universität Regensburg entstanden: | Ja | ||||||||||
| Dokumenten-ID: | 4677 |
Web of ScienceZusammenfassung
The bioisosteric replacement of the guanidino group in arpromidine-like histamine H-2 receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and blood-brain barrier penetration. Unfortunately, the selectivity of such N-G-acylated imidazolylpropylguanidines for the H2R is poor, in particular versus histamine H-3 ...
Zusammenfassung
The bioisosteric replacement of the guanidino group in arpromidine-like histamine H-2 receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and blood-brain barrier penetration. Unfortunately, the selectivity of such N-G-acylated imidazolylpropylguanidines for the H2R is poor, in particular versus histamine H-3 (H3R) and H-4 receptors (H4R). This drawback appears to depend on the "privileged" imidozolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H2R-selective histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H2R agonists. The aminothiazoles are nearly equipotent to the corresponding imidozoles as H2R ogonists. Compared with histamine, the potency is increased up to 40-fold on the guinea pig right atrium, and up to 125- and 280-fold in GTPase assays with human and guinea pig H2R-G(s alpha s) fusion proteins expressed in SO insect cells, respectively. Docking studies on H2R models support the hypothesis that 2-aminothiazolyl and imidozolyl derivatives interact with H(2)Rs as bioisosteres. In contrast to the imidozoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H-1, H-3, and H-4 receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H2R agonism of N-G-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.
Metadaten zuletzt geändert: 29 Sep 2021 07:28
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