Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse

DeLuca A, Pierno S, Natuzzi F, Franchini C, Duranti A, Lentini G, Tortorella V, Jockusch H, Camerino DC (1997)
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 282(1): 93-100.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Autor*in
DeLuca, A; Pierno, S; Natuzzi, F; Franchini, C; Duranti, A; Lentini, G; Tortorella, V; Jockusch, HaraldUniBi; Camerino, DC
Abstract / Bemerkung
To search for use-dependent sodium channel blockers to selectively solve skeletal muscle hyperexcitability in hereditary myotonias, mexiletine (MEX; compound I) and its newly synthetized analogs, 2-(4-chloro-2-methylphenoxy)-benzenethanamine (compound II) and (-)-S-3-(2,6-dimethylphenoxy)-2-methylpropanamine (compound III), were tested on intercostal muscle fibers from the myotonic ADR mouse through use of the standard current-clamp microelectrode technique. in parallel, the effects of these compounds on the sodium channels were measured on frog muscle fibers under voltage-clamp conditions. The tonic and use-dependent blocks of peak sodium currents (I-Namax) produced by each compound were evaluated by using a single depolarizing pulse and a pulse train at 10 Hz frequency, respectively. At 10 and 50 mu M, MEX decreased the occurrence of spontaneous excitability in myotonic muscle fibers; 100 mu M was required to decrease the amplitude of the action potential and the stimulus-induced firing of the membrane as well as to increase the threshold for generation of action potential. At 300 mu M, MEX decreased the latency of the action potential and increased the threshold current to elicit a single action potential. MEX produced a tonic block of I-Namax with an half-maximal concentration (IC50) of 83 mu M, but the IC50 value for use-dependent block was 3-fold lower. Compound III, which differs from MEX in that it has a longer alkyl chain, similarly blocked first the spontaneous and then the stimulus-evoked excitability of myotonic muscle fibers but at 2-fold lower concentrations than MEX. Compound III was less potent than MEX in producing a tonic block of I-Namax (IC50 = 108 mu M) but was a strong use-dependent blocker with an IC50 close to 15 mu M. The more lipophylic compound II irreversibly blocked both spontaneous and stimulus-evoked membrane excitability at concentrations as low as 10 mu M and shortened the latency of the action potential in a concentration-dependent fashion. Compound II produced a potent tonic block of I-Namax (IC50 = 30 mu M), and its potency increased 2-fold during high-frequency stimulation. Both of the new analogs (compound II in particular), but not MEX, were less effective on the excitability parameters of striated fibers of healthy vs. ADR mice, a characteristic that increases their interest as potential antimyotonic agents.
Erscheinungsjahr
1997
Zeitschriftentitel
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Band
282
Ausgabe
1
Seite(n)
93-100
ISSN
0022-3565
Page URI
https://pub.uni-bielefeld.de/record/1627852

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DeLuca A, Pierno S, Natuzzi F, et al. Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 1997;282(1):93-100.
DeLuca, A., Pierno, S., Natuzzi, F., Franchini, C., Duranti, A., Lentini, G., Tortorella, V., et al. (1997). Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 282(1), 93-100.
DeLuca, A, Pierno, S, Natuzzi, F, Franchini, C, Duranti, A, Lentini, G, Tortorella, V, Jockusch, Harald, and Camerino, DC. 1997. “Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse”. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 282 (1): 93-100.
DeLuca, A., Pierno, S., Natuzzi, F., Franchini, C., Duranti, A., Lentini, G., Tortorella, V., Jockusch, H., and Camerino, D. C. (1997). Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 282, 93-100.
DeLuca, A., et al., 1997. Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 282(1), p 93-100.
A. DeLuca, et al., “Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse”, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 282, 1997, pp. 93-100.
DeLuca, A., Pierno, S., Natuzzi, F., Franchini, C., Duranti, A., Lentini, G., Tortorella, V., Jockusch, H., Camerino, D.C.: Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 282, 93-100 (1997).
DeLuca, A, Pierno, S, Natuzzi, F, Franchini, C, Duranti, A, Lentini, G, Tortorella, V, Jockusch, Harald, and Camerino, DC. “Evaluation of the antimyotonic activity of mexiletine and some new analogs on sodium currents of single muscle fibers and on the abnormal excitability of the myotonic ADR mouse”. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 282.1 (1997): 93-100.

19 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.
De Bellis M, Carbonara R, Roussel J, Farinato A, Massari A, Pierno S, Muraglia M, Corbo F, Franchini C, Carratù MR, De Luca A, Conte Camerino D, Desaphy JF., Neuropharmacology 113(pt a), 2017
PMID: 27743929
Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential.
De Bellis M, Sanarica F, Carocci A, Lentini G, Pierno S, Rolland JF, Conte Camerino D, De Luca A., Front Pharmacol 8(), 2017
PMID: 29379434
Effect of mexiletine on transitory depression of compound motor action potential in recessive myotonia congenita.
Lo Monaco M, D'Amico A, Luigetti M, Desaphy JF, Modoni A., Clin Neurophysiol 126(2), 2015
PMID: 25065301
Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated Ir(III) catalysts.
Talwar D, Poyatos Salguero N, Robertson CM, Xiao J., Chemistry 20(1), 2014
PMID: 24516890
Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels.
De Bellis M, De Luca A, Desaphy JF, Carbonara R, Heiny JA, Kennedy A, Carocci A, Cavalluzzi MM, Lentini G, Franchini C, Camerino DC., Biophys J 104(2), 2013
PMID: 23442856
Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs.
Carocci A, Catalano A, Bruno C, Lentini G, Franchini C, De Bellis M, De Luca A, Conte Camerino D., Chirality 22(3), 2010
PMID: 19544349
Spiroborate ester-mediated asymmetric synthesis of beta-hydroxy ethers and its conversion to highly enantiopure beta-amino ethers.
Huang K, Ortiz-Marciales M, Correa W, Pomales E, López XY., J Org Chem 74(11), 2009
PMID: 19413288
Neuroprotective effect of mexiletine in the central nervous system of diabetic rats.
Ates O, Cayli SR, Altinoz E, Yucel N, Kocak A, Tarim O, Durak A, Turkoz Y, Yologlu S., Mol Cell Biochem 286(1-2), 2006
PMID: 16541198
New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse.
De Luca A, Pierno S, Liantonio A, Desaphy JF, Natuzzi F, Didonna MP, Ferrannini E, Jockusch H, Franchini C, Lentini G, Corbo F, Tortorella V, Camerino DC., Neuromuscul Disord 14(7), 2004
PMID: 15210163
Inhibition of skeletal muscle sodium currents by mexiletine analogues: specific hydrophobic interactions rather than lipophilia per se account for drug therapeutic profile.
De Luca A, Talon S, De Bellis M, Desaphy JF, Franchini C, Lentini G, Catalano A, Corbo F, Tortorella V, Conte-Camerino D., Naunyn Schmiedebergs Arch Pharmacol 367(3), 2003
PMID: 12644906
Ion channels in muscle and cardiac hereditary diseases: from gene dysfunction to pharmacological therapy. 10-11 March 2000, Bari, Italy.
Desaphy JF, De Luca A, Tricarico D, Pierno S, Conte Camerino D., Neuromuscul Disord 11(6-7), 2001
PMID: 11525889
Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na(+) channels enhancing the antimyotonic activity in vivo.
Talon S, De Luca A, De Bellis M, Desaphy JF, Lentini G, Scilimati A, Corbo F, Franchini C, Tortorella P, Jockusch H, Conte Camerino D., Br J Pharmacol 134(7), 2001
PMID: 11724759
Homologation of mexiletine alkyl chain and stereoselective blockade of skeletal muscle sodium channels.
Duranti A, Franchini C, Lentini G, Loiodice F, Tortorella V, De Luca A, Pierno S, Conte Camerino D., Eur J Med Chem 35(1), 2000
PMID: 10733611
Facile entry to (-)-(R)- and (+)-(S)-mexiletine.
Carocci A, Franchini C, Lentini G, Loiodice F, Tortorella V., Chirality 12(3), 2000
PMID: 10689287
Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX.
Desaphy JF, Conte Camerino D, Franchini C, Lentini G, Tortorella V, De Luca A., Br J Pharmacol 128(6), 1999
PMID: 10578128
Effects of mexiletine on ATP sensitive K+ channel of rat skeletal muscle fibres: a state dependent mechanism of action.
Tricarico D, Barbieri M, Franchini C, Tortorella V, Camerino DC., Br J Pharmacol 125(4), 1998
PMID: 9831925
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