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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

Schematic model of the sub-processes of drug access. An illustration of the hypothetical sub-processes of drug access that must be supposed based on experimental data: (1) partitioning of the charged molecule at the outer membrane interface; (2) protonation/deprotonation in the extracellular space; (3) partitioning of the neutral molecule at the outer membrane interface; (4) protonation/deprotonation at the outer membrane interface; (5) entry/exit through the fenestration (hydrophobic pathway); (6) protonation/deprotonation within the inner vestibule; (7) protonation/deprotonation at the inner membrane interface; (8) intracellular diffusion; (9) entry/exit through the activation gate (hydrophilic pathway).
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Figure 4: Schematic model of the sub-processes of drug access. An illustration of the hypothetical sub-processes of drug access that must be supposed based on experimental data: (1) partitioning of the charged molecule at the outer membrane interface; (2) protonation/deprotonation in the extracellular space; (3) partitioning of the neutral molecule at the outer membrane interface; (4) protonation/deprotonation at the outer membrane interface; (5) entry/exit through the fenestration (hydrophobic pathway); (6) protonation/deprotonation within the inner vestibule; (7) protonation/deprotonation at the inner membrane interface; (8) intracellular diffusion; (9) entry/exit through the activation gate (hydrophilic pathway).

Mentions: We will discuss six major phenomena that could be quantified from the amplitude plots. We attempted to synthesize the observations, and place them into a framework of a general hypothesis regarding the major steps along the access pathway of drugs toward the binding site. All assumed sub-processes of drug access and egress, which may be of different importance depending on the chemical nature of individual compounds are summarized in Figure 4. Our major findings are summarized in Figure 5, which: (in the 2nd column) shows a characteristic occurrence of each observed phenomenon chosen from Figure 1 (or Supplemental Figure 1); lists the major chemical properties which seem to determine their occurrence (3rd column); and shows a graphic representation of their hypothetical explanation (4th column).


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)

Schematic model of the sub-processes of drug access. An illustration of the hypothetical sub-processes of drug access that must be supposed based on experimental data: (1) partitioning of the charged molecule at the outer membrane interface; (2) protonation/deprotonation in the extracellular space; (3) partitioning of the neutral molecule at the outer membrane interface; (4) protonation/deprotonation at the outer membrane interface; (5) entry/exit through the fenestration (hydrophobic pathway); (6) protonation/deprotonation within the inner vestibule; (7) protonation/deprotonation at the inner membrane interface; (8) intracellular diffusion; (9) entry/exit through the activation gate (hydrophilic pathway).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Schematic model of the sub-processes of drug access. An illustration of the hypothetical sub-processes of drug access that must be supposed based on experimental data: (1) partitioning of the charged molecule at the outer membrane interface; (2) protonation/deprotonation in the extracellular space; (3) partitioning of the neutral molecule at the outer membrane interface; (4) protonation/deprotonation at the outer membrane interface; (5) entry/exit through the fenestration (hydrophobic pathway); (6) protonation/deprotonation within the inner vestibule; (7) protonation/deprotonation at the inner membrane interface; (8) intracellular diffusion; (9) entry/exit through the activation gate (hydrophilic pathway).
Mentions: We will discuss six major phenomena that could be quantified from the amplitude plots. We attempted to synthesize the observations, and place them into a framework of a general hypothesis regarding the major steps along the access pathway of drugs toward the binding site. All assumed sub-processes of drug access and egress, which may be of different importance depending on the chemical nature of individual compounds are summarized in Figure 4. Our major findings are summarized in Figure 5, which: (in the 2nd column) shows a characteristic occurrence of each observed phenomenon chosen from Figure 1 (or Supplemental Figure 1); lists the major chemical properties which seem to determine their occurrence (3rd column); and shows a graphic representation of their hypothetical explanation (4th column).

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