Ghorai, Prasanta and Kraus, Anja and Keller, Max and Goette, Carsten and Igel, Patrick and Schneider, Erich and Schnell, David and Bernhardt, Guenther and Dove, Stefan and Zabel, Manfred and Elz, Sigurd and Seifert, Roland and Buschauer, Armin (2008) Acylguanidines as Bioisosteres of Guanidines: N-G-Acylated Imidazolylpropylguanidines, a New Class of Histamine H-2 Receptor Agonists. JOURNAL OF MEDICINAL CHEMISTRY, 51 (22). pp. 7193-7204. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
N-1-Aryl(heteroaryl)alkyl-N-2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H-2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH(1)R and hH(3)R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH(4)R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; CONSTITUTIVE ACTIVITY; INTERNATIONAL UNION; HUMAN-NEUTROPHILS; CRYSTAL-STRUCTURE; H-2 RECEPTORS; HUMAN BRAIN; GUINEA-PIG; ANTAGONISTS; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 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) Chemistry and Pharmacy > Institut für Anorganische Chemie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Oct 2020 06:12 |
| Last Modified: | 19 Oct 2020 06:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30036 |
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