Abstract
The solvation of prilocaine has been investigated in pure water and in an amphiphilic methanol/water solution using a combination of neutron diffraction with isotopic substitution augmented by Empirical Potential Structure Refinement (EPSR) simulations. This combination of techniques allows for details of the solvation structure on the atomic scale to be unravelled. The hydration of prilocaine is significantly altered relative to when this molecule is in pure water (as a hydrochloride salt) or in an amphiphilic environment (as a freebase compound). Interestingly, there is not a significant change in hydration around the amine group on prilocaine hydrochloride compared with prilocaine as a freebase. Despite this group being an ammonium group in water and an amine group in methanol/water solutions, the hydration of this motif remains largely intact. The changes in hydration between prilocaine as a free base and prilocaine·HCl instead appears to arise from a change in hydration around the aromatic ring and the amide group in the prilocaine molecule.
Highlights
Even though it is generally agreed that local anaesthetics (LA) function by disrupting the transfer of ions across membranes,[1] the precise mechanism of action of local anaesthetics remains largely unknown.[2]
The individual site–site radial distribution functions (RDFs) can be extracted from Empirical Potential Structure Refinement (EPSR) and the coordination numbers (nba(r)) of these functions can be determined from integration via ð rmax nba ðrÞ 1⁄4 4prcb r2gabðrÞdr: (3)
It is clear that the hydration of prilocaine changes relative to when this molecule is in only water or in aqueous amphiphilic environment
Summary
Even though it is generally agreed that local anaesthetics (LA) function by disrupting the transfer of ions across membranes,[1] the precise mechanism of action of local anaesthetics remains largely unknown.[2]. A full understanding of the underlying mechanisms of this phenomenon is crucial as a substantial number of drugs fail due to inadequate BBB permeability.[11,12,13] Given that biological and physiological processes mostly take place in an aqueous or partly aqueous amphiphilic environment such as membranes,[14] understanding how pharmaceuticals behave in solutions of similar characteristics is of utter importance for drug development
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