Membrane Interactivity of Anesthetic Adjuvant Dexmedetomidine Discriminable from Clonidine and Enantiomeric Levomedetomidine

Aims: Dexmedetomidine, which has been increasingly used as an anesthetic adjuvant, is more lipophilic and more active than another α2-adrenergic agonist clonidine and enantiomeric levomedetomidine. Lipophilicity and stereostructure affect the clinical effects of α2-adrenergic agonists. We aimed to compare the membrane interactivity of dexmedetomidine with clonidine and levomedetomidine from a point of view different from the mode of action on α2-adrenergic receptors.

Methodology: Unilamellar vesicles were prepared with phospholipids and cholesterol to mimic the lipid compositions of peripheral nerve cell, central nerve cell and cardiomyocyte membranes, and lipid rafts. They were subjected to the reactions with dexmedetomidine, clonidine and levomedetomidine at 10-200 μM, followed by measuring fluorescence polarization to determine the membrane interactivity to change membrane fluidity and specify the membrane region for the stereostructure-specific interaction.

Results: Dexmedetomidine and clonidine acted on lipid bilayers to increase the membrane fluidity with potencies varying by a compositional difference of membrane lipids. Dexmedetomidine showed greater interactivity with neuro-mimetic and cardiomyocyte-mimetic membranes than clonidine, being consistent with their comparative lipophilicity and activity. The effects of α2-adrenergic agonists on lipid raft model membranes were much weaker than those on other membranes, indicating that lipid rafts are not mechanistically relevant to them. Higher interactive dexmedetomidine was discriminated from lower interactive levomedetomidine in the presence of chiral cholesterol in membranes. An interactivity difference between two enantiomers was largest in the superficial region of lipid bilayers and the rank order of their membrane-interacting potency was reversed by replacing cholesterol with epicholesterol, suggesting that cholesterol’s 3β-hydroxyl groups positioned close to the membrane surface are responsible for the enantioselective interaction.

Conclusion: Dexmedetomidine structure-specifically interacts with biomimetic membranes depending on their lipid compositions more potently than clonidine and levomedetomidine. Such membrane interactivity associated with higher lipophilicity and stereostructure characterizes dexmedetomidine in addition to higher affinity for α2-adrenergic receptors.