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

1 Searching for the structural requirements improving the potency and the s tereoselectivity of Na+ channel blockers as antimyotonic agents, new deriva tives of tocainide, in which the chiral carbon atom is constrained in a rig id alpha -proline or pyrrolo-imidazolic cycle, were synthesized as pure ena ntiomers. 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 investi gated in vitro on single fibres of frog semitendinosus muscle using the vas eline-gap voltage-clamp method. 3 The alpha -proline derivative, To5, was 5 and 21 fold more potent than to cainide in producing tonic and 10 Hz-use-dependent block, respectively. Com pared to To5, the presence of one methyl group on the aminic (To6) or amidi c (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectiv ely. When methylene moieties were present on both nitrogen atoms (To8), bot h 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 rigi dity as in pyrrolo-imidazolic derivatives markedly decreased the drug poten cy with respect to tocainide. 5 Antimyotonic activity, evaluated as the shortening of the time of rightin g 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 blocker s with improved therapeutic potential.