Tropmann, Katharina and Bresinsky, Merlin and Forster, Lisa and Moennich, Denise and Buschauer, Armin and Wittmann, Hans-Joachim and Huebner, Harald and Gmeiner, Peter and Pockes, Steffen and Strasser, Andrea (2021) Abolishing Dopamine D-2long/D-3 Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H-2 Receptor Agonists. JOURNAL OF MEDICINAL CHEMISTRY, 64 (12). pp. 8684-8709. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H-2 receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D-2-like receptors (especially to the D3R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H1-4 and D-2(lon)g/3 receptors. This study revealed a couple of selective candidates (among others 31 and 47), and the most promising ones were screened at several off-target receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H2- and D-2(lon)g/3-receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LEVODOPA-INDUCED DYSKINESIA; HIGH CONSTITUTIVE ACTIVITY; CONSERVED SERINE RESIDUES; SITE-DIRECTED MUTAGENESIS; BINDING SITE; G-PROTEIN; PHARMACOLOGICAL CHARACTERIZATION; INTERNATIONAL UNION; MUTATIONAL ANALYSIS; ACHE INHIBITOR; |
| 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: | 09 Sep 2022 10:10 |
| Last Modified: | 09 Sep 2022 10:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46903 |
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