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Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

Lazar A, Lenkey N, Pesti K, Fodor L, Mike A - Front Pharmacol (2015)

Bottom Line: 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.We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics.Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation.

View Article: PubMed Central - PubMed

Affiliation: Intensive Care Unit, University of Medicine and Pharmacy Tirgu Mures, Romania.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Chemical properties affecting alkalization-induced recovery. Neutral-to-alkalic solution exchange-induced recovery plotted against logP.
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Figure 9: Chemical properties affecting alkalization-induced recovery. Neutral-to-alkalic solution exchange-induced recovery plotted against logP.

Mentions: If “acidification-induced-recovery” was essentially equivalent with “decreased alkalic recovery,” then one could expect that “alkalization-induced-recovery” should be equivalent with “decreased acidic recovery,” and therefore we should best see alkalization-induced-recovery with compounds that are prone to accumulate in the hydrophilic trap, i.e., relatively hydrophilic, polar drugs with a relatively low pKa. This, however, was absolutely not what we found. In fact the compounds that showed “decreased acidic recovery” (either a tendency or a significant difference) failed to display at the same time “alkalization-induced recovery” (with the only exception of nefazodone). These typically small, polar, relatively hydrophilic compounds, with a substantial neutral fraction at pH = 7.3, were fully released by neutralization, and alkalization did not further help their escape. The compounds that needed alkalization to be released, were to be found in the “low acidic recovery” group, these compounds had low reversibility at both acidic and neutral pH, and therefore, perfusion of neutral medium could not release them fully. As we have mentioned, they were chemically different from the “decreased acidic recovery” group, most of them being highly lipophilic (Figure 9). Of the compounds with the 7 highest logP values, 5 showed prominent alkalization-induced recovery (sertraline, nefazodone, ritanserin, maprotiline, and chlorpromazine). These are the exact same compounds, which had low reversibility values (<0.6) under all three pH conditions. In the case of nisoxetine (logP = 3.14) the phenomenon was small and only significant at p = 0.05 level. We suppose that for this group of compounds both lipophilic and hydrophilic interactions contributed to binding. The finding that high lipophilicity was a requirement for both acidification and alkalization-induced recovery suggests that the same lipophilic drug may exhibit both phenomena. Indeed, all six compounds showed enhanced recovery both upon neutral-to-alkalic and alkalic-to-neutral transitions (Supplemental Figure 1).


Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

Lazar A, Lenkey N, Pesti K, Fodor L, Mike A - Front Pharmacol (2015)

Chemical properties affecting alkalization-induced recovery. Neutral-to-alkalic solution exchange-induced recovery plotted against logP.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585259&req=5

Figure 9: Chemical properties affecting alkalization-induced recovery. Neutral-to-alkalic solution exchange-induced recovery plotted against logP.
Mentions: If “acidification-induced-recovery” was essentially equivalent with “decreased alkalic recovery,” then one could expect that “alkalization-induced-recovery” should be equivalent with “decreased acidic recovery,” and therefore we should best see alkalization-induced-recovery with compounds that are prone to accumulate in the hydrophilic trap, i.e., relatively hydrophilic, polar drugs with a relatively low pKa. This, however, was absolutely not what we found. In fact the compounds that showed “decreased acidic recovery” (either a tendency or a significant difference) failed to display at the same time “alkalization-induced recovery” (with the only exception of nefazodone). These typically small, polar, relatively hydrophilic compounds, with a substantial neutral fraction at pH = 7.3, were fully released by neutralization, and alkalization did not further help their escape. The compounds that needed alkalization to be released, were to be found in the “low acidic recovery” group, these compounds had low reversibility at both acidic and neutral pH, and therefore, perfusion of neutral medium could not release them fully. As we have mentioned, they were chemically different from the “decreased acidic recovery” group, most of them being highly lipophilic (Figure 9). Of the compounds with the 7 highest logP values, 5 showed prominent alkalization-induced recovery (sertraline, nefazodone, ritanserin, maprotiline, and chlorpromazine). These are the exact same compounds, which had low reversibility values (<0.6) under all three pH conditions. In the case of nisoxetine (logP = 3.14) the phenomenon was small and only significant at p = 0.05 level. We suppose that for this group of compounds both lipophilic and hydrophilic interactions contributed to binding. The finding that high lipophilicity was a requirement for both acidification and alkalization-induced recovery suggests that the same lipophilic drug may exhibit both phenomena. Indeed, all six compounds showed enhanced recovery both upon neutral-to-alkalic and alkalic-to-neutral transitions (Supplemental Figure 1).

Bottom Line: 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.We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics.Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation.

View Article: PubMed Central - PubMed

Affiliation: Intensive Care Unit, University of Medicine and Pharmacy Tirgu Mures, Romania.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus