| Item type: | Article | ||||||
|---|---|---|---|---|---|---|---|
| Journal or Publication Title: | Journal of Medicinal Chemistry | ||||||
| Publisher: | AMER CHEMICAL SOC | ||||||
| Place of Publication: | WASHINGTON | ||||||
| Volume: | 52 | ||||||
| Number of Issue or Book Chapter: | 20 | ||||||
| Page Range: | pp. 6297-6313 | ||||||
| Date: | 30 September 2009 | ||||||
| Additional Information (public): | Supporting Information available online | ||||||
| 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) | ||||||
| Projects (Historical): | GRK 760, Graduiertenkolleg Medizinische Chemie | ||||||
| Identification Number: |
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| Related URLs: |
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| Keywords: | G-ACYLATED IMIDAZOLYLPROPYLGUANIDINES; HIGH CONSTITUTIVE ACTIVITY; PHARMACOLOGICAL CHARACTERIZATION; MOLECULAR-CLONING; HUMAN EOSINOPHILS; 1ST POTENT; AB-INITIO; H-2-RECEPTOR; BINDING; ANTAGONIST; | ||||||
| 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: | 6012 |
Web of ScienceAbstract
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, ...
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).
Metadata last modified: 29 Sep 2021 07:28
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