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Title: The search for novel histamine H3 receptor ligands in the group of piperazine derivatives
Abstract:
The overall aim of this work was to obtain a series of novel, active and selective, histamine H3 receptor ligands, whilst maintaining a favorable physicochemical properties and ADMET parameters. Two previously described compounds from the H3R ligands library obtained in the Department of Technology and Biotechnology of Drugs – DL76 and DL77, were selected as lead structures for further modifications. As a result of this work, a total of eighty new piperazine derivatives were synthesized. Structure–activity studies allowed for the establishment of the 4-pyridylpiperazine moiety as a new bioisosteric piperidine replacement in H3R ligands. The results of the in vitro tests proved this scaffold being a crucial element for high hH3R affinity. Global analysis of collected data referring to influence of alkyl linker length, allowed for the selection of three methylene homologues, due to their highest H3R affinity values among all described 4-pyridylpiperazine derivatives. Interestingly, benzophenone derivative 65 (KSK63) showed the highest affinity among all tested compounds (hH3R Ki = 3.12 nM). Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Additional, pro-cognitive properties of compound 9 (KSK19) were confirmed in the passive avoidance test. Consequently, 9 has been chosen as a new lead stru ; cture and therefore proceeded to further studies, including its potential anti-obesity activity. Animals fed with high-fat diet and treated with 9 showed significantly less weight gain, in comparison with the control group.
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Rada Dyscypliny Nauki farmaceutyczne
Promoter:
Kieć-Kononowicz, Katarzyna ; Kuder, Kamil
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Last modified:
Apr 8, 2024
In our library since:
Apr 4, 2022
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All available object's versions:
http://dl.cm-uj.krakow.pl:8080/publication/4613
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| Edition name | Date |
|---|---|
| ZB-132353 | Apr 8, 2024 |
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