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

Abstract

1 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 a-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers.2 Their ability to block Na + currents, elicited from 7100 to 720 mV at 0.3 Hz (tonic block) and 2 ± 10 Hz (use-dependent block) frequencies, was investigated in vitro on single ®bres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method.3 The a-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. 4 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. 5 Antimyotonic activity, evaluated as the shortening of the time of righting re¯exes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more eective for R-To5 than for RTocainide. 6 Thus, constraining the chiral centre of tocainide in a-proline cycle leads to more potent and stereoselective use-dependent Na + channel blockers with improved therapeutic potential.

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

“…2, each drug produced a block of sodium currents that was generally more pronounced at the HP of Ϫ70 mV than at Ϫ140 mV. In accordance with previous results (Talon et al, 2001), the ␣-proline derivative To5 at 100 M produced a block of I Na that was comparable with that produced by 500 M Toc. Interestingly, the ␤-prolineanalog To9 showed almost the same potency as To5, suggesting that the increased distance of the amino group by one methylene does not greatly modify the interaction of this constrained molecule with the receptor.…”

“…In line with the more strict spatial conformation, the ␣ proline-like analog of tocainide, conventionally named To5, showed an increased stereoselectivity. In parallel, the eutomer (R)-To5 was 5-and 20-fold more potent than tocainide in producing a tonic and a 10-Hz use-dependent block of sodium currents, respectively (Talon et al, 2001). These findings suggest a better interaction of the pharmacophoric groups with the binding site.…”

“…However, the chiral center is strictly adjacent to the amino group; thus, the above-described changes could lead to a general amelioration of the binding properties of the main pharmacophore. Interesting results were obtained by constraining the stereogenic center and the amino group in a proline-like cycle (Talon et al, 2001). In line with the more strict spatial conformation, the ␣ proline-like analog of tocainide, conventionally named To5, showed an increased stereoselectivity.…”

“…In fact, according to previous data Talon et al, 2001), To5 showed a higher pK a than Toc, and the homologating of the amino group by one methylene further increases the basicity. As generally observed for tertiary amines compared with secondary amines in an aqueous environment (Aue et al, 1972), Benzyl-To5 and Benzyl-To9 were less basic than the respective nonbenzylated analogs.…”

“…The results shed further light on the molecular interaction of LAs with their receptor. Also, the new potent agents deserve further investigation for their wide potential therapeutic application, because previous studies indicate a good correlation between the scale of potency determined by this approach and the in vivo and in vitro antimyotonic activity of the drugs in animal models of the human disease (De Luca et al, 1997b;Talon et al, 2001). …”