Igel, Patrick and Geyer, Roland and Strasser, Andrea and Dove, Stefan and Seifert, Roland and Buschauer, Armin (2009) Synthesis and Structure-Activity Relationships of Cyanoguanidine-Type and Structurally Related Histamine H-4 Receptor Agonists. JOURNAL OF MEDICINAL CHEMISTRY, 52 (20). pp. 6297-6313. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
Recently, we identified high-affinity human histamine H-3 (hH(3)R) and H-4 receptor (hH(4)R) ligands among a series of N-G-acylated imidazolylpropylguanidines, which were originally designed as histamine H-2 receptor (H2R) agonists. Aiming at selectivity for hH(4)R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH(4)R agonist (pEC(50) = 7.47, alpha = 0.93) showing negligible hH(1)R and hH(2)R activities and significant selectivity over the hH(3)R (pK(B) = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using. membrane preparations of hH(x)R-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH(4)R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH(3)R inverse agonist (pK(B) = 8.42, > 300-fold selectivity over the other HR subtypes).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | G-ACYLATED IMIDAZOLYLPROPYLGUANIDINES; HIGH CONSTITUTIVE ACTIVITY; PHARMACOLOGICAL CHARACTERIZATION; MOLECULAR-CLONING; HUMAN EOSINOPHILS; 1ST POTENT; AB-INITIO; H-2-RECEPTOR; BINDING; ANTAGONIST; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Sep 2020 06:52 |
| Last Modified: | 03 Sep 2020 06:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28260 |
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