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, et al. (2004)
NEUROMUSCULAR DISORDERS 14(7): 405-416.

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Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Abstract / Bemerkung
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. Tot 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. (C) 2004 Elsevier B.V. All rights reserved.
Erscheinungsjahr
Zeitschriftentitel
NEUROMUSCULAR DISORDERS
Band
14
Zeitschriftennummer
7
Seite
405-416
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De Luca A, Pierno S, Liantonio A, et al. New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse. NEUROMUSCULAR DISORDERS. 2004;14(7):405-416.
De Luca, A., Pierno, S., Liantonio, A., Desaphy, J. F., Natuzzi, F., Didonna, M. P., Ferrannini, E., et al. (2004). New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse. NEUROMUSCULAR DISORDERS, 14(7), 405-416. doi:10.1016/j.nmd.2004.04.006
De Luca, A., Pierno, S., Liantonio, A., Desaphy, J. F., Natuzzi, F., Didonna, M. P., Ferrannini, E., Jockusch, H., Franchini, C., Lentini, G., et al. (2004). New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse. NEUROMUSCULAR DISORDERS 14, 405-416.
De Luca, A., et al., 2004. New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse. NEUROMUSCULAR DISORDERS, 14(7), p 405-416.
A. De Luca, et al., “New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse”, NEUROMUSCULAR DISORDERS, vol. 14, 2004, pp. 405-416.
De Luca, A., Pierno, S., Liantonio, A., Desaphy, J.F., Natuzzi, F., Didonna, M.P., Ferrannini, E., Jockusch, H., Franchini, C., Lentini, G., Corbo, F., Tortorella, V., Camerino, D.C.: New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse. NEUROMUSCULAR DISORDERS. 14, 405-416 (2004).
De Luca, A, Pierno, S, Liantonio, A, Desaphy, JF, Natuzzi, F, Didonna, MP, Ferrannini, E, Jockusch, Harald, Franchini, C, Lentini, G, Corbo, F, Tortorella, V, and Camerino, DC. “New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse”. NEUROMUSCULAR DISORDERS 14.7 (2004): 405-416.

11 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
Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery.
Imbrici P, Liantonio A, Camerino GM, De Bellis M, Camerino C, Mele A, Giustino A, Pierno S, De Luca A, Tricarico D, Desaphy JF, Conte D., Front Pharmacol 7(), 2016
PMID: 27242528
Sodium channel slow inactivation as a therapeutic target for myotonia congenita.
Novak KR, Norman J, Mitchell JR, Pinter MJ, Rich MM., Ann Neurol 77(2), 2015
PMID: 25515836
Taurine: the appeal of a safe amino acid for skeletal muscle disorders.
De Luca A, Pierno S, Camerino DC., J Transl Med 13(), 2015
PMID: 26208967
Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.
Signore S, Sorrentino A, Borghetti G, Cannata A, Meo M, Zhou Y, Kannappan R, Pasqualini F, O'Malley H, Sundman M, Tsigkas N, Zhang E, Arranto C, Mangiaracina C, Isobe K, Sena BF, Kim J, Goichberg P, Nahrendorf M, Isom LL, Leri A, Anversa P, Rota M., Nat Commun 6(), 2015
PMID: 26541940
In vivo evaluation of antimyotonic efficacy of β-adrenergic drugs in a rat model of myotonia.
Desaphy JF, Costanza T, Carbonara R, Conte Camerino D., Neuropharmacology 65(), 2013
PMID: 23000075
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
Searching for novel anti-myotonic agents: pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide.
De Luca A, De Bellis M, Corbo F, Franchini C, Muraglia M, Catalano A, Carocci A, Camerino DC., Neuromuscul Disord 22(1), 2012
PMID: 21802953
Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.
Statland JM, Bundy BN, Wang Y, Rayan DR, Trivedi JR, Sansone VA, Salajegheh MK, Venance SL, Ciafaloni E, Matthews E, Meola G, Herbelin L, Griggs RC, Barohn RJ, Hanna MG, Consortium for Clinical Investigation of Neurologic Channelopathies., JAMA 308(13), 2012
PMID: 23032552
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

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