Local Anesthetics Transfer Across the Membrane: Reproducing Octanol-Water Partition Coefficients by Solvent Reaction Field Methods

Abstract

Local anesthetics are one of the most widely used drug classes in clinical practice. Like many other biological molecules, their properties are altered depending on their protonation status, which is dependent on the pH of the environment. We studied the transport energetics of seven local anesthetics from the extracellular fluid across the biological membrane to the axoplasm in order to understand the effect of pH value on their efficacy and other pharmaco-dynamic roperties. In this we applied three different methods of solvent reaction field in conjunction with quantum chemical calculations to reproduce experimental values of n-octanol/water partition coefficients for both neutral and protonated forms. Only the SMD method of Cramer and Truhlar was able to reproduce experimental partition coefficient values. The results are discussed in terms of the function of local anesthetics under physiological conditions and in the case of local acidosis.

The effects of biologically important divalent and trivalent metal cations on the cyclization step of dopamine autoxidation reaction: A quantum chemical study

“…Calculations of pKa values are very demanding and can serve as one of the strictest tests for the efficiency of various solvation models (Kavcic et al, 2021;Repicˇet al, 2014;Warshel, 1981). Our results show that the calculated pKa value of dopamine o-quinone (pKa calc = 8.73) is in good agreement with the experimental pKa value of dopamine (pKa exp = 8.86) (Berfield et al, 1999) showing that the SMD reaction field solvation model with M06/Def2-TZVPP level of theory is sufficiently accurate.…”

Protonation and orientation: a computational approach to cocaine diffusion through a model membrane

“…In a similar sense, this also holds for aqueous phases with different pH values. Partition coefficients stemming from experiments 30 or reaction field computations 31 can be used in a thermodynamic model to compute the pH-dependent distribution of anesthetics in detail. 32 While we qualitatively discuss pH effects, the main focus of our work is on the transfer dynamics and its time scale.…”

Antioxidant activity of lidocaine, bupivacaine, and ropivacaine in aqueous and lipophilic environments: an experimental and computational study

“…The effects of solvation were considered by applying the universal solvation model (SMD) ( Marenich et al, 2009 ). We chose the SMD solvation model because, in our previous studies, it was found to be the most accurate in reproducing the solvation effects of local anesthetics and other organic molecules ( Umek, 2020 ; Kavčič et al, 2021a ; Umek, 2022 ). In this study, we considered two solvents: water with a dielectric constant of 78.30 and n-octanol with a dielectric constant of 9.86.…”