Abstract
To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.
Highlights
Motion sickness can be caused by traveling, such as ship, car, train, air or space motion, and virtual reality immersion like watching the 3D stereoscopic films
The stereoselective differences of phencynonate isomers were investigated in terms of their in vivo pharmacokinetic characteristics and their tissue distribution kinetics especially in brain, indicating that there were some marked differences in the main kinetic parameters of S- and R-phencynonate[15]
The studies have suggested that there are in vivo metabolic and active differences existing between S- and R-phencynonate, up to date, there are no articles about the stereoselective mechanisms on the drug activity for anti-motion sickness, receptor affinity, chiral drug metabolism, transport, protein binding, and molecular docking between phencynonate isomers and muscarinic acetylcholine receptor (mAChR)
Summary
Motion sickness can be caused by traveling, such as ship, car, train, air or space motion, and virtual reality immersion like watching the 3D stereoscopic films. Scopolamine is the most effective prophylactic agent for short (4 to 6-hour) exposures to severe motion, and probably for exposures of up to several days These agents have obvious side effects, such as antagonism on central nervous system (e.g. sedation, drowsiness)[6], and seriously limit their wide use on people conducting important social activities or precise tasks. Various configurations affect pharmacological and toxicological activities, mainly caused by receptor affinity and activity, drug transport, metabolism and/or pharmacokinetics[16,17]. The studies have suggested that there are in vivo metabolic and active differences existing between S- and R-phencynonate, up to date, there are no articles about the stereoselective mechanisms on the drug activity for anti-motion sickness, receptor affinity, chiral drug metabolism, transport, protein binding, and molecular docking between phencynonate isomers and mAChR. The current results showed valuable evidence for the development of a novel chiral eutomer drug for the prevention and/or treatment of motion sickness
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