Geyer, Roland and Kaske, Melanie and Baumeister, Paul and Buschauer, Armin (2014) Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H-3 and H-4 Receptor Ligands. ARCHIV DER PHARMAZIE, 347 (2). pp. 77-88. ISSN 0365-6233, 1521-4184
Full text not available from this repository. (Request a copy)Abstract
Imbutamine (4-(1H-imidazol-4-yl) butanamine) is a potent histamine H-3 (H3R) and H-4 receptor (H4R) agonist (EC50 values: 3 and 66nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [S-35] GTP gamma S binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, alpha = 0.8) was equipotent with imbutamine at the hH(4)R, but revealed about 16-fold selectivity for the hH(4)R compared to the hH(3)R (EC50 980 nM, alpha = 0.36), whereas imbutamine preferred the hH(3)R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | H4 RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; H-2-RECEPTOR AGONISTS; MOLECULAR-CLONING; CELL-MIGRATION; 1ST POTENT; ANTAGONISTS; GUANIDINES; MODULATION; EXPRESSION; Bioisosteres; H-3 receptor; H-4 receptor; Histamine; Imbutamine |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Nov 2019 10:21 |
| Last Modified: | 27 Nov 2019 10:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10691 |
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