Abolishing Dopamine D2long/D3 Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2 Receptor Agonists
| Autor: | Merlin Bresinsky, Lisa Forster, Steffen Pockes, Denise Mönnich, Andrea Strasser, Harald Hübner, Peter Gmeiner, Katharina Tropmann, Hans-Joachim Wittmann, Armin Buschauer |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Chemistry Central nervous system Subtype selective 01 natural sciences Affinities 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences medicine.anatomical_structure Histamine H2 receptor Biochemistry Docking (molecular) Dopamine receptor D3 Dopamine Drug Discovery medicine Molecular Medicine Receptor 030304 developmental biology medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 64:8684-8709 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00692 |
| Popis: | 3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H2 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 D2-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 D2long/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 D2long/3-receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies. |
| Databáze: | OpenAIRE |
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