Kraus, Anja and Ghorai, Prasanta and Birnkammer, Tobias and Schnell, David and Elz, Sigurd and Seifert, Roland and Dove, Stefan and Bernhardt, Guenther and Buschauer, Armin (2009) N-G-Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H-2 Receptor Agonists. CHEMMEDCHEM, 4 (2). pp. 232-240. ISSN 1860-7179,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RECEPTOR; H-1-RECEPTOR; PHARMACOLOGY; HISTAMINE-H2-RECEPTOR; GUANIDINES; AMTHAMINE; LIGANDS; MODELS; acylguanidines; aminothiazoles; GTPase; medicinal chemistry; receptors; structure-activity relationships |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Oct 2020 11:05 |
| Last Modified: | 06 Oct 2020 11:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/29495 |
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