INHIBITION OF FROG SKELETAL-MUSCLE SODIUM-CHANNELS BY NEWLY SYNTHESIZED CHIRAL DERIVATIVES OF MEXILETINE AND TOCAINIDE

To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthe sized chiral analogs of mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by v aseline-gap voltage clamp method. The effect of each drug on the maxim al peak Na+ transient (I-Na max) was evaluated as both tonic and use-d ependent block by using infrequent depolarizing stimulation and trains of pulses at 2-10 Hz frequency, respectively. The mexiletine analog 3 -(2, 6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent tha n mexiletine in producing a tonic block but produced a remarkable use- dependent block. In fact, the half-maximal concentration (IC50) for to nic block of S(-)-Me2 was 108 mu M vs. 54.5 mu M of R(-)-mexiletine, b ut the IC50 was 6.2 times lowered by the 10 Hz stimulation with respec t to the 2.4fold decrease observed with mexiletine. The R(-)-mexiletin e and the S(-)-Me2 were about twofold more potent than the correspondi ng enantiomers in producing a tonic block, but the stereoselectivity a ttenuated during use-dependent blockade. The more lipophilic 2-(4-chlo ro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as r aceme, produced a potent and irreversible tonic block of the sodium cu rrents with an IC50 of 29 mu M, but had a less pronounced use-dependen t inhibition, with a 1.9fold decrease of the IC50 at 10 Hz. The R(-) i somer of 2',6'-valinoxylidide (To1), a tocainide derivative with an in creased hindrance on the chiral carbon atom, was twofold (IC50 209 mu M) and tenfold (IC50 = 27.4 mu M) more potent than R(-)-tocainide in t onic and use-dependent block, respectively. Tocainide was almost devoi d of stereoselectivity, whereas the eudismic ratio of Tol [(IC50 S(+)- To1/LC50 R(-)-To1] was 1.7. As for mexiletine and Me2, the stereoselec tivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 mu M, and 1 min stimulation at 10 Hz was needed to show up a 50% block of I-Na max. All the compounds produced a left-shi ft of the steady-state inactivation curve correlated positively with t he extent of use-dependent inhibition, with the exception of the cycli c To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and Tol might be premising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomita ntly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skelet al muscle sodium channels.