| Item type: | Article | ||||||||||
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| Journal or Publication Title: | ChemMedChem | ||||||||||
| Publisher: | WILEY-BLACKWELL | ||||||||||
| Place of Publication: | MALDEN | ||||||||||
| 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 > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) | ||||||||||
| Projects (Historical): | GRK 760, Graduiertenkolleg Medizinische Chemie | ||||||||||
| Identification Number: |
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| Related URLs: |
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| Keywords: | RECEPTOR; H-1-RECEPTOR; PHARMACOLOGY; HISTAMINE-H2-RECEPTOR; GUANIDINES; AMTHAMINE; LIGANDS; MODELS; acylguanidines; aminothiazoles; GTPase; medicinal chemistry; receptors; structure-activity relationships | ||||||||||
| Dewey Decimal Classification: | 600 Technology > 615 Pharmacy 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 |
Web of ScienceAbstract
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 ...
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.
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