Abolishing Dopamine D2long/D3Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2Receptor Agonists

Tropmann K, Bresinsky M, Forster L, Mönnich D, Buschauer A, Wittmann HJ, Hübner H, Gmeiner P, Pockes S, Strasser A (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Medicinal Chemistry American Chemical Society

DOI: 10.1021/acs.jmedchem.1c00692

Abstract

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.

Authors with CRIS profile

Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Universität Regensburg DE Germany (DE)

How to cite

APA:

Tropmann, K., Bresinsky, M., Forster, L., Mönnich, D., Buschauer, A., Wittmann, H.J.,... Strasser, A. (2021). Abolishing Dopamine D2long/D3Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2Receptor Agonists. Journal of Medicinal Chemistry. https://dx.doi.org/10.1021/acs.jmedchem.1c00692

MLA:

Tropmann, Katharina, et al. "Abolishing Dopamine D2long/D3Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H2Receptor Agonists." Journal of Medicinal Chemistry (2021).

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