Bartole, Edith and Littmann, Timo and Tanaka, Miho and Ozawa, Takeaki and Buschauer, Armin and Bernhardt, Guenther (2019) [H-3]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H-4 Receptors. JOURNAL OF MEDICINAL CHEMISTRY, 62 (17). pp. 8338-8356. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H-4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH(4)Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH(4)Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC(50) (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC(50) (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([H-3]46) at the h/m/rH(4)Rs revealed comparable K-d values (41/17/22 nM), low nonspecific binding (11-17%, similar to K-d), and fast associations/dissociations (25-30 min) and disclosed [H-3]UR-DEBa176 as useful molecular tool to determine h/m/rH(4)R binding affinities for H4R ligands.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HIGH CONSTITUTIVE ACTIVITY; PHARMACOLOGICAL CHARACTERIZATION; MOLECULAR DETERMINANTS; FUNCTIONAL SELECTIVITY; 1ST POTENT; AGONIST; CLONING; H-2-RECEPTOR; LIGANDS; H-4-RECEPTOR; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Apr 2020 09:16 |
| Last Modified: | 06 Apr 2020 09:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26261 |
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