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

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 α‐proline or pyrrolo‐imidazolic cycle, were synthesized as pure enantiomers. 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. The α‐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. 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. 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. Thus, constraining the chiral centre of tocainide in α‐proline cycle leads to more potent and stereoselective use‐dependent Na + channel blockers with improved therapeutic potential.British Journal of Pharmacology (2001) 134 , 1523–1531; doi: 10.1038/sj.bjp.0704366