Key result
The pH-dependence of 30 sodium channel inhibitors showed diverse patterns not solely correlated with pKa, suggesting drug molecules can be trapped in hydrophilic and lipophilic environments along the access pathway.
The diverse pH-sensitivity patterns of sodium channel inhibitors suggest that drug access and affinity are determined by complex interactions with both hydrophilic and lipophilic environments along the access pathway.
May inform Na channel blocker effects in acidic conditions; leaves open clinical translation of the proposed trap model.
The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.
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Lazăr et al. (2015) studied Sodium channel inhibition. 30 sodium channel inhibitors vs. Different pH levels (6.0, 7.3, 8.6) was evaluated on pH-dependence of potency, reversibility, and onset/offset kinetics. The pH-dependence of 30 sodium channel inhibitors showed diverse patterns not solely correlated with pKa, suggesting drug molecules can be trapped in hydrophilic and lipophilic environments along the access pathway.
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