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Giovanni Lentini - One of the best experts on this subject based on the ideXlab platform.
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synthesis and toxicopharmacological evaluation of m hydroxyMexiletine the first metabolite of Mexiletine more potent than the parent compound on voltage gated sodium channels
Journal of Medicinal Chemistry, 2012Co-Authors: Alessia Catalano, Jean François Desaphy, Giovanni Lentini, Alessia Carocci, Antonia Di Mola, Claudio Bruno, Roberta Carbonara, Annalisa De Palma, Roberta Budriesi, Carla GhelardiniAbstract:The first synthesis of m-hydroxyMexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent Mexiletine and to have more favorable toxicological properties than Mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of Mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.
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new potent Mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic adr mouse
Neuromuscular Disorders, 2004Co-Authors: Annamaria De Luca, Jean François Desaphy, Carlo Franchini, Mp Didonna, Sabata Pierno, Antonella Liantonio, F Natuzzi, Ermanno Ferrannini, Harald Jockusch, Giovanni LentiniAbstract:The antimyotonic activity of chiral derivatives of Mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of Mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than Mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than Mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.
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optically active Mexiletine analogues as stereoselective blockers of voltage gated na channels
Journal of Medicinal Chemistry, 2003Co-Authors: Carlo Franchini, Paolo Tortorella, D. Conte Camerino, Alessia Catalano, Giovanni Lentini, Alessia Carocci, Maria Maddalena Cavalluzzi, Filomena Corbo, Antonio Scilimati, Annamaria De LucaAbstract:Optically active Mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The Mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of Mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than Mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for Mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-Mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with Mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for Mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.
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inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of Mexiletine and tocainide
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: Annamaria De Luca, Vincenzo Tortorella, Giovanni Lentini, Carlo Franchini, F Natuzzi, Giulia Falcone, A Duranti, Conte D CamerinoAbstract:To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of Mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (INa max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2–10 Hz frequency, respectively. The Mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than Mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(–)-Me2 was 108 μM vs. 54.5 μM of R(–)-Mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4fold decrease observed with Mexiletine. The R(–)-Mexiletine and the S(–)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 μM, but had a less pronounced use-dependent inhibition, with a 1.9fold decrease of the IC50 at 10 Hz. The R(–) isomer of 2′,6′-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 μM) and tenfold (IC50 = 27.4 μM) more potent than R(–)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(–)-To1] was 1.7. As for Mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 μM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of INa max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.
Jean François Desaphy - One of the best experts on this subject based on the ideXlab platform.
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Effect of Mexiletine on transitory depression of compound motor action potential in recessive myotonia congenita
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 2014Co-Authors: Mauro Lo Monaco, Jean François Desaphy, Adele D'amico, Marco Luigetti, Anna ModoniAbstract:Abstract Objective We aim to demonstrate the effect of Mexiletine on the compound muscle action potential (CMAP) amplitude transitory depression (TD) in a cohort of patients with recessive myotonia congenita. Methods We evaluated 21 patients with recessive myotonia congenita referred to our institute from 1990 to 2013 and treated with Mexiletine chlorhydrate. All patients underwent prolonged 3Hz repetitive nerve stimulation (3Hz-PLRS) before and after the beginning of treatment. Results We observed in all subjects a reduction of CMAP amplitude TD after the beginning of treatment. The mean value of the TD nadir before starting Mexiletine treatment was −62.0% and reduced to −28.8% after the therapy was started (51.6% reduction, p Conclusions The 3Hz-PLRS is configured as a neurophysiological test able to indirectly detect and quantify, through the measurement of TD, the clinical phenomenon of the transitory weakness that occurs in myotonic syndromes due to CLCN1 mutations. Significance This neurophysiological test might be considered a helpful tool to assess the effect of anti-myotonic drugs, as Mexiletine, in recessive myotonia congenita.
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synthesis and toxicopharmacological evaluation of m hydroxyMexiletine the first metabolite of Mexiletine more potent than the parent compound on voltage gated sodium channels
Journal of Medicinal Chemistry, 2012Co-Authors: Alessia Catalano, Jean François Desaphy, Giovanni Lentini, Alessia Carocci, Antonia Di Mola, Claudio Bruno, Roberta Carbonara, Annalisa De Palma, Roberta Budriesi, Carla GhelardiniAbstract:The first synthesis of m-hydroxyMexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent Mexiletine and to have more favorable toxicological properties than Mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of Mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.
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new potent Mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic adr mouse
Neuromuscular Disorders, 2004Co-Authors: Annamaria De Luca, Jean François Desaphy, Carlo Franchini, Mp Didonna, Sabata Pierno, Antonella Liantonio, F Natuzzi, Ermanno Ferrannini, Harald Jockusch, Giovanni LentiniAbstract:The antimyotonic activity of chiral derivatives of Mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of Mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than Mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than Mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.
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Gating of myotonic Na channel mutants defines the response to Mexiletine and a potent derivative
Neurology, 2001Co-Authors: Jean François Desaphy, A. De Luca, Paolo Tortorella, D De Vito, Alfred L. George, D. Conte CamerinoAbstract:Background: Myotonia and periodic paralysis caused by sodium channel mutations show variable responses to the anti-myotonic drug Mexiletine. Objective: To investigate whether variability among sodium channel mutants results from differences in drug binding affinity or in channel gating. Methods: Whole-cell sodium currents (I Na ) were recorded in tsA201 cells expressing human wild-type (WT) and mutant skeletal muscle sodium channels (A1156T, hyperkalemic periodic paralysis; R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia). Results: At a holding potential (hp) of −120 mV, Mexiletine produced a tonic (TB, 0.33 Hz) and a use-dependent (UDB, 10 Hz) block of peak I Na with a potency following the order rank R1448C > WT ≈ A1156T > G1306E. Yet, when assayed from an hp of −180 mV, TB and UDB by Mexiletine were similar for the four channels. The different midpoints of channel availability curves found for the four channels track the half-maximum inhibitory value (IC 50 ) measured at −120 mV. Thus differences in the partitioning of channels between the closed and fast-inactivated states underlie the different IC 50 measured at a given potential. The Mexiletine-derivative, Me7 (α-[(2-methylphenoxy)methyl]-benzenemethanamine), behaved similarly but was ∼5 times more potent than Mexiletine. Interestingly, the higher drug concentrations ameliorated the abnormally slower decay rate of myotonic I Na . Conclusions: These results explain the basis of the apparent difference in block of mutant sodium channels by Mexiletine and Me7, opening the way to a more rationale drug use and to design more potent drugs able to correct specifically the biophysical defect of the mutation in individual myotonic patients.
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effect of Mexiletine on sea anemone toxin induced non inactivating sodium channels of rat skeletal muscle a model of sodium channel myotonia
Neuromuscular Disorders, 1999Co-Authors: Jean François Desaphy, Conte D Camerino, Vincenzo Tortorella, A. De LucaAbstract:Abstract The sea anemone toxin ATX II impairs skeletal muscle sodium channel inactivation, mimicking the persistent inward current observed in patients suffering from sodium channel myotonia. Mexiletine has beneficial effects on myotonia. To verify the efficiency of the drug on persistent inward current, we investigated the effect of 50 μ M R(−)-Mexiletine on sodium channels in cell-attached patches of rat skeletal muscle fibres, in the absence or presence of 2 μ M ATX II. With the toxin, a proportion of channels displayed remarkable abnormal activity lasting the entire depolarisation, which resulted in a persistent inward current that represented up to 2.0% of the peak current. Mexiletine reduced by 75% the peak current elicited by depolarisation from −100 to −20 mV. This was due to the reduction by 60% of the maximal available peak current I max and to the negative shift by −7 mV of steady-state inactivation. Mexiletine also greatly decreased the late current, but the effect was limited to 60% of reduction, comparable to that on I max . Therefore Mexiletine was able to block the ATX II-modified sodium channels, inhibiting the myotonia-producing persistent inward current.
Annamaria De Luca - One of the best experts on this subject based on the ideXlab platform.
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new potent Mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic adr mouse
Neuromuscular Disorders, 2004Co-Authors: Annamaria De Luca, Jean François Desaphy, Carlo Franchini, Mp Didonna, Sabata Pierno, Antonella Liantonio, F Natuzzi, Ermanno Ferrannini, Harald Jockusch, Giovanni LentiniAbstract:The antimyotonic activity of chiral derivatives of Mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of Mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than Mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than Mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.
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optically active Mexiletine analogues as stereoselective blockers of voltage gated na channels
Journal of Medicinal Chemistry, 2003Co-Authors: Carlo Franchini, Paolo Tortorella, D. Conte Camerino, Alessia Catalano, Giovanni Lentini, Alessia Carocci, Maria Maddalena Cavalluzzi, Filomena Corbo, Antonio Scilimati, Annamaria De LucaAbstract:Optically active Mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The Mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of Mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than Mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for Mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-Mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with Mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for Mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.
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inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of Mexiletine and tocainide
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: Annamaria De Luca, Vincenzo Tortorella, Giovanni Lentini, Carlo Franchini, F Natuzzi, Giulia Falcone, A Duranti, Conte D CamerinoAbstract:To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of Mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (INa max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2–10 Hz frequency, respectively. The Mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than Mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(–)-Me2 was 108 μM vs. 54.5 μM of R(–)-Mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4fold decrease observed with Mexiletine. The R(–)-Mexiletine and the S(–)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 μM, but had a less pronounced use-dependent inhibition, with a 1.9fold decrease of the IC50 at 10 Hz. The R(–) isomer of 2′,6′-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 μM) and tenfold (IC50 = 27.4 μM) more potent than R(–)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(–)-To1] was 1.7. As for Mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 μM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of INa max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.
Carlo Franchini - One of the best experts on this subject based on the ideXlab platform.
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new potent Mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic adr mouse
Neuromuscular Disorders, 2004Co-Authors: Annamaria De Luca, Jean François Desaphy, Carlo Franchini, Mp Didonna, Sabata Pierno, Antonella Liantonio, F Natuzzi, Ermanno Ferrannini, Harald Jockusch, Giovanni LentiniAbstract:The antimyotonic activity of chiral derivatives of Mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of Mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than Mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than Mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.
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optically active Mexiletine analogues as stereoselective blockers of voltage gated na channels
Journal of Medicinal Chemistry, 2003Co-Authors: Carlo Franchini, Paolo Tortorella, D. Conte Camerino, Alessia Catalano, Giovanni Lentini, Alessia Carocci, Maria Maddalena Cavalluzzi, Filomena Corbo, Antonio Scilimati, Annamaria De LucaAbstract:Optically active Mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The Mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of Mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than Mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for Mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenylethanamine [(R)-3b], was 27-fold more potent than (R)-Mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with Mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for Mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.
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inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of Mexiletine and tocainide
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: Annamaria De Luca, Vincenzo Tortorella, Giovanni Lentini, Carlo Franchini, F Natuzzi, Giulia Falcone, A Duranti, Conte D CamerinoAbstract:To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of Mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (INa max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2–10 Hz frequency, respectively. The Mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than Mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(–)-Me2 was 108 μM vs. 54.5 μM of R(–)-Mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4fold decrease observed with Mexiletine. The R(–)-Mexiletine and the S(–)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 μM, but had a less pronounced use-dependent inhibition, with a 1.9fold decrease of the IC50 at 10 Hz. The R(–) isomer of 2′,6′-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 μM) and tenfold (IC50 = 27.4 μM) more potent than R(–)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(–)-To1] was 1.7. As for Mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 μM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of INa max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.
Jonathan R Strayer - One of the best experts on this subject based on the ideXlab platform.
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effect of Mexiletine on spinal cord injury dysesthetic pain
American Journal of Physical Medicine & Rehabilitation, 1996Co-Authors: Faye Y Chioutan, Stephen M Tuel, Jane C Johnson, Michael M Priebe, David D Hirsh, Jonathan R StrayerAbstract:Severe pain occurs in 5-30% of the spinal cord-injured (SCI) population and is difficult to treat. Subarachnoid lidocaine has been used in selected patients with some success. Mexiletine, an analog of lidocaine that acts at Na+/K+ channels in the peripheral nerve, has been found effective in persons with diabetic dysesthetic neuropathy. The effect of Mexiletine in the treatment of spinal cord dysesthetic pain was examined in this study. Fifteen patients were enrolled, and 11 patients completed the prospective, randomized, placebo-controlled, double-blind, crossover design trial. Inclusion/exclusion criteria were carefully defined. A 1-wk washout period was followed by a 4-wk drug trial of either Mexiletine (450 mg/day) or placebo. This was repeated for the second medication in the second arm of the study. Patients were followed weekly with McGill and visual analog pain scales. Baseline, midpoint, and endpoint Barthel function scores were recorded. The Wilcoxon's signed-rank test and paired t test were used for statistical analysis. Results showed no significant effect of Mexiletine on SCI dysesthetic pain scales or Barthel index. In conclusion, in this trial, Mexiletine did not appear to decrease spinal cord injury-related dysesthetic pain.