Vol. 282, Issue 1, 93-100, 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 Mouse¹

Annamaria De Luca, Sabata Pierno, Fedele Natuzzi, Carlo Franchini, Andrea Duranti, Giovanni Lentini, Vincenzo Tortorella, Harald Jockusch and Diana Conte Camerino

Unit of Pharmacology, Department of Pharmacobiology (A.D.L., S.P., F.N., D.C.C.), and Department of Medicinal Chemistry (C.F., A.D., G.L., V.T.), Faculty of Pharmacy, University of Bari, 70125 Italy, and Developmental Biology Unit (H.J.), W7, University of Bielefeld, D-33501, Germany

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 µM, MEX decreased the occurrence of spontaneous excitability in myotonic muscle fibers; 100 µM 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 µM, 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 µM, 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 µM) but was a strong use-dependent blocker with an IC₅₀ close to 15 µM. The more lipophylic compound II irreversibly blocked both spontaneous and stimulus-evoked membrane excitability at concentrations as low as 10 µM 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 µM), 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.