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- Title
Benzophenone Derivatives with Histamine H 3 Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease.
- Authors
Godyń, Justyna; Zaręba, Paula; Stary, Dorota; Kaleta, Maria; Kuder, Kamil J.; Latacz, Gniewomir; Mogilski, Szczepan; Reiner-Link, David; Frank, Annika; Doroz-Płonka, Agata; Olejarz-Maciej, Agnieszka; Sudoł-Tałaj, Sylwia; Nolte, Tobias; Handzlik, Jadwiga; Stark, Holger; Więckowska, Anna; Malawska, Barbara; Kieć-Kononowicz, Katarzyna; Łażewska, Dorota; Bajda, Marek
- Abstract
The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10−6 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.
- Subjects
HISTAMINE receptors; ALZHEIMER'S disease; TACRINE; LIGANDS (Biochemistry); HISTAMINE; LIVER microsomes; PERMEABILITY
- Publication
Molecules, 2023, Vol 28, Issue 1, p238
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules28010238