Interaction With the Lipid Membrane Influences Fentanyl Pharmacology.

Autor:	Sutcliffe KJ; School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom., Corey RA; Department of Biochemistry, Medical Sciences Division, University of Oxford, Oxford, United Kingdom., Alhosan N; School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom., Cavallo D; School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom., Groom S; Department of Pharmacy and Pharmacology, Faculty of Science, University of Bath, Bath, United Kingdom., Santiago M; Macquarie Medical School, Macquarie University, Sydney, NSW, Australia., Bailey C; Department of Pharmacy and Pharmacology, Faculty of Science, University of Bath, Bath, United Kingdom., Charlton SJ; Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom., Sessions RB; School of Biochemistry, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom., Henderson G; School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom., Kelly E; School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom.
Jazyk:	angličtina
Zdroj:	Advances in drug and alcohol research [Adv Drug Alcohol Res] 2022 Mar 21; Vol. 2.
DOI:	10.3389/adar.2022.10280
Abstrakt:	Overdose deaths from fentanyl have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist that is less well reversed by naloxone than morphine. Due to fentanyl's high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by its interactions with the lipid membrane on route to binding to the μ-opioid receptor (MOPr). Through coarse-grained molecular dynamics simulations, electrophysiological recordings and cell signalling assays, we determined how fentanyl and morphine access the orthosteric pocket of MOPr. Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl may take a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices. In electrophysiological recordings fentanyl-induced currents returned after washout, suggesting fentanyl deposits in the lipid membrane. However, mutation of residues forming the potential MOPr transmembrane access site did not alter fentanyl's pharmacological profile in vitro . A high local concentration of fentanyl in the lipid membrane, possibly in combination with a novel lipophilic binding route, may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone. Competing Interests: Conflict Of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Databáze:	MEDLINE
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