Dual‐Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H₃ Receptor Antagonistic and Anticholinesterase Activity

Abstract

The study presents novel biological properties of diether derivatives of homo- or substituted piperidine ligands of the histamine H(3) receptor. The compounds were evaluated for their inhibitory potency against acetylcholinesterase (AChE) from the electric eel and butyrylcholinesterase (BuChE) from horse serum. The most interesting multifunctional compound 13 displayed high affinity for the cloned hH(3) R (K(i) = 3.48 nM) and moderate inhibitory potency against both enzymes (IC(50) AChE = 7.91 µM and BuChE = 4.97 µM). Molecular modeling studies revealed interactions with key amino acid residues in the homology model of histamine H(3) receptor ligands, as well as the binding model for AChE and BuChE in the catalytic and peripheral active sites.

Histamine H3 receptor ligands by hybrid virtual screening, docking, molecular dynamics simulations, and investigation of their biological effects

“…The results of docking indicate that the critical amino acids interacting with different parts of selected molecules are as follows: Glu 206 (TM5) in the interaction with basic moiety, Tyr 115 (TM3) and Tyr 374 (TM6) residues interact with linker, and Tyr 189 (TM5) and Phe 398 (TM7) forms the hydrophobic pocket with hydrophobic/aromatic moiety ( Figure S3.1). These findings are in close agreement with the findings published previously (Axe et al, 2006;Bajda et al, 2012;Harusawa et al, 2013;Kuder et al, 2016;Łażewska et al, 2016;Lepailleur et al, 2014;Levoin et al, 2013;Morini et al, 2006;Sheng et al, 2015;Wen et al, 2017).…”

Structure-based discovery and binding site analysis of histamine receptor ligands

“…At the top 80% of the ranked database 11.4% and 23% decoys were found for the randomly selected and focused decoys, respectively. Prospective screening on this model yielded seven virtual hits that were tested in a Another bovine rhodopsin based model of H3R was published by Bajda et al [34]. In their study the binding mode of selected diether derivatives of piperidine and homopiperidine was analyzed.…”

Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties

“…Considering both H 3 R and ChE are involved in the regulation of the amount of ACh, dual‐active acetylcholinesterase (AChE) inhibitors and H 3 R antagonists have been developed in several groups . Previous SARs on numerous H 3 R ligands indicated that O ‐ and N ‐substituted 4‐amino‐3‐(aminomethyl)phenyl ethers possess high H 3 R binding affinity and antagonist potency, particularly as 3‐(piperidin‐1‐yl)propyl ether and with a tertiary amino methyl in position 3 ( 12 – 14 , Fig.…”