Synthesis of new 2,6-prolylxylidide analogues of tocainide as stereoselective blockers of voltage-gated Na(+) channels with increased potency and improved use-dependent activity.

摘要: A series of tocainide chiral analogues were designed, synthesized, and evaluated in vitro, pure enantiomeric form, as use-dependent blockers skeletal muscle sodium channels to better understand the structural requirements responsible for antimyotonic activity. The voltage clamp recordings showed a remarkable increase both potency behavior with analogue N-(2, 6-dimethylphenyl)-2-pyrrolidinecarboxamide (1a). In fact (R)-1a was 5-fold more potent than (R)-tocainide producing tonic block, i.e., reduction peak current resting conditions after application compound, but it 21-fold condition high frequency stimulation (phasic block). Furthermore, opposite tocainide, this compound also stereoselective, (S)-1a being 2-3-fold less (R)-1a. introduction 1a methyl group place hydrogen bonded either aminic nitrogen atom [N-(2, 6-dimethylphenyl)-1-methyl-2-pyrrolidinecarboxamide (2a)] or amidic 6-dimethylphenyl)-N-methyl-2-pyrrolidinecarboxamide (3a)] led unexpectedly an inversion stereoselectivity, (S)-enantiomers 3-fold (R)-ones. comparison between eutomers that (S)-2a (S)-3a are almost equieffective half-maximal concentrations about 100 microM; however, remarkably decreased by presence group: gain observed at amounted 3 1.6 times 2a 3a, respectively. replacement hydrogens atoms resulted N-(2,6-dimethylphenyl)-N, 1-dimethyl-2-pyrrolidinecarboxamide (4a) which (S)-isomer still twice (R)-one, absolute mostly strongly reduced, showing therefore no clear advantages respect tocainide. behavior, plays pivotal role activity, is reduced groups on atoms, likely modification pK(a) and/or constraint molecular conformation.