



Item type: | Article | ||||
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Journal or Publication Title: | European Journal of Medicinal Chemistry | ||||
Publisher: | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | ||||
Place of Publication: | ISSY-LES-MOULINEAUX | ||||
Volume: | 213 | ||||
Page Range: | p. 113041 | ||||
Date: | 2021 | ||||
Institutions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) | ||||
Identification Number: |
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Keywords: | DRUG-LIKENESS; H3 RECEPTOR; BODY-WEIGHT; FOOD-INTAKE; IN-VITRO; DERIVATIVES; TARGET; IDALOPIRDINE; PHARMACOLOGY; INHIBITION; Histamine H-3 receptor; Non-imidazole histamine H3R ligands; Piperazine derivatives, Selective ligands; Molecular docking; Anti-obesity agents | ||||
Dewey Decimal Classification: | 600 Technology > 615 Pharmacy | ||||
Status: | Published | ||||
Refereed: | Yes, this version has been refereed | ||||
Created at the University of Regensburg: | Partially | ||||
Item ID: | 51104 |
Abstract
A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H-3 receptor (H3R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H3R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the ...

Abstract
A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H-3 receptor (H3R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H3R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H3R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H3R (K-i = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H-3 receptor. While its structural replacement to piperidine is also tolerated for H3R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H3R, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. (C) 2020 Elsevier Masson SAS. All rights reserved.
Metadata last modified: 02 Dec 2021 10:59