| Item type: | Article | ||||||||||
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| Journal or Publication Title: | ChemMedChem | ||||||||||
| Publisher: | Wiley VCH | ||||||||||
| Volume: | 4 | ||||||||||
| Number of Issue or Book Chapter: | 2 | ||||||||||
| Page Range: | pp. 232-240 | ||||||||||
| Date: | 13 February 2009 | ||||||||||
| Additional Information (public): | Online publiziert am 15. Dezember 2008 | ||||||||||
| Institutions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) | ||||||||||
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| Keywords: | bioisosterism; structure-activity relationships; histamine H2 receptor; histamine H2 receptor agonist; acylguanidines; receptor selectivity GTPase assay aminothiazoles | ||||||||||
| Dewey Decimal Classification: | 500 Science > 570 Life sciences 500 Science > 540 Chemistry & allied sciences | ||||||||||
| Status: | Published | ||||||||||
| Refereed: | Yes, this version has been refereed | ||||||||||
| Created at the University of Regensburg: | Yes | ||||||||||
| Item ID: | 4677 |
Abstract
The bioisosteric replacement of the guanidino group in arpromidine-like histamine H2 receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and penetration across the blood brain barrier. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropyl-guanidines for the H2R is poor, in particular versus ...
Abstract
The bioisosteric replacement of the guanidino group in arpromidine-like histamine H2 receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and penetration across the blood brain barrier. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropyl-guanidines for the H2R is poor, in particular versus histamine H3 (H3R) and H4 receptors (H4R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine 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 with the corresponding imidazoles as H2R agonists. Compared to histamine, the potency is increased up to 40-fold on the guinea pig right atrium and up to 125- and 280-fold, respectively, in GTPase assays at human and guinea pig H2R-GsαS fusion proteins expressed in Sf9 insect cells. Docking studies on H2R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H2Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H1, H3 and H4 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.
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