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, Camerino DC (2001)
BRITISH JOURNAL OF PHARMACOLOGY 134(7): 1523-1531.

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1 Searching for the structural requirements improving the potency and the stereoselectivity of Na+ channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid alpha -proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. 2 Their ability to block Na+ currents, elicited from -100 to -20 mV at 0.3 Hz (tonic block) and 2-10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. 3 The alpha -proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. 4 Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. 5 Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. 6 Thus, constraining the chiral centre of tocainide in alpha -proline cycle leads to more potent and stereoselective use-dependent Na+ channel blockers with improved therapeutic potential.
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Talon S, De Luca A, De Bellis M, et al. 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. BRITISH JOURNAL OF PHARMACOLOGY. 2001;134(7):1523-1531.
Talon, S., De Luca, A., De Bellis, M., Desaphy, J. F., Lentini, G., Scilimati, A., Corbo, F., et al. (2001). 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. BRITISH JOURNAL OF PHARMACOLOGY, 134(7), 1523-1531.
Talon, S., De Luca, A., De Bellis, M., Desaphy, J. F., Lentini, G., Scilimati, A., Corbo, F., Franchini, C., Tortorella, P., Jockusch, H., et al. (2001). 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. BRITISH JOURNAL OF PHARMACOLOGY 134, 1523-1531.
Talon, S., et al., 2001. 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. BRITISH JOURNAL OF PHARMACOLOGY, 134(7), p 1523-1531.
S. Talon, et al., “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”, BRITISH JOURNAL OF PHARMACOLOGY, vol. 134, 2001, pp. 1523-1531.
Talon, S., De Luca, A., De Bellis, M., Desaphy, J.F., Lentini, G., Scilimati, A., Corbo, F., Franchini, C., Tortorella, P., Jockusch, H., Camerino, D.C.: 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. BRITISH JOURNAL OF PHARMACOLOGY. 134, 1523-1531 (2001).
Talon, S, De Luca, A, De Bellis, M, Desaphy, JF, Lentini, G, Scilimati, A, Corbo, F, Franchini, C, Tortorella, P, Jockusch, Harald, and Camerino, DC. “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”. BRITISH JOURNAL OF PHARMACOLOGY 134.7 (2001): 1523-1531.
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5 Citations in Europe PMC

Data provided by Europe PubMed Central.

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Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents.
Catalano A, Carocci A, Corbo F, Franchini C, Muraglia M, Scilimati A, De Bellis M, De Luca A, Camerino DC, Sinicropi MS, Tortorella V., Eur J Med Chem 43(11), 2008
PMID: 18342401
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

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