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Optimal Requirements for High Affinity and Use-Dependent Block of Skeletal Muscle Sodium Channel by N-Benzyl Analogs of Tocainide-Like Compounds

Unità di Farmacologia, Dipartimento Farmacobiologico (A.D.L., S.T., M.D.B., J.-F.D., D.C.C.) and Dipartimento Farmacochimico (G.L., F.C., A.S., C.F., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (I_Na) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). I_Na were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking I_Na at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked I_Na with a half-maximal concentration of 0.5 µM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pK_a value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.

Address correspondence to: Prof. Diana Conte Camerino, Unità di Farmacologia, Dipartimento Farmacobiologico, Facoltà di Farmacia, University di Bari, Via Orabona 4, Campus 70121, Bari, Italy. E-mail: conte{at}farmbiol.uniba.it

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