Biselli, Sabrina and Bresinsky, Merlin and Tropmann, Katharina and Forster, Lisa and Honisch, Claudia and Buschauer, Armin and Bernhardt, Gunther and Pockes, Steffen (2021) Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 214: 113190. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)Abstract
Even today, the role of the histamine H-2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pK(i) = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [S-35]GTP gamma S and beta-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pK(i) (139, UR-KAT523): 8.35; pK(i) (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH(2)R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD(2long)R and agonists with high affinity at the hD(3)R (e.g. pKi (139, UR-KAT523): 7.80; pK(i) (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS. (C) 2021 Elsevier Masson SAS. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; Histamine H-2 receptor; Receptor subtype selectivity; Dopamine D-2long receptor; Dopamine D-3 receptor; Carbamoylguanidines; Aminothiazoles |
| 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 13:25 |
| Last Modified: | 09 Sep 2022 13:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46959 |
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