Blockers of Skeletal Muscle Nav1.4 Channels: From Therapy of Myotonic Syndrome to Molecular Determinants of Pharmacological Action and Back

Figures

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  Figure 1. Structure of the human Nav1.4-b1 complex. (A) Side and (B) top view of the human Nav1.4-b1 complex (pdb: 6AGF; [64]). The VSDs are colored yellow, orange, green and violet. The S5–S6 helices are colored cyan. The IFM motif is shown as blue spheres, and the III-IV linker is colored blue. (C) Schematic representation of an NaVCh undergoing the major gating transitions.

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  Figure 2. Chemical structure of Mexiletine and its newly synthesized analogs. The boxes show the most interesting compounds with the ratio between IC50 values during tonic block (TB) and use-dependent block at the frequency of 10 hertz (UDB) (IC50 TB/IC50 UDB 10-Hz). The ratio is shown to allow an easier comparison of the use-dependent behavior of each compound [87].

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  Figure 3. Chemical structure of Tocainide and its newly synthesized analogs. The boxes show the most interesting compounds with the ratio between IC50 values during tonic block (TB) and use-dependent block at the frequency of 10 hertz (UDB) (IC50 TB/IC50 UDB 10-Hz). The ratio is shown to allow an easier comparison of the use-dependent behavior of each compound [89,90].

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  Figure 4. Tonic and use-dependent block exerted by Toc analogues (To040 and To042). (A) Traces of sodium current transients recorded in the absence and presence of the test compounds 500 μM Toc, 3 μM To040 and 3 μM To042. (B) Concentration-response curves for 10-Hz use-dependent block of sodium currents obtained with Toc, To40 and To42 [96].

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  Figure 5. Tonic and use-dependent block exerted by Mex analogues (VM11 and CI16). (A) Traces of sodium current transients recorded in the absence and presence of the test compounds 100 μM Mex, 10 μM VM11 and 10 μM CI16. (B) Concentration-response curves for 10-Hz use-dependent block of sodium currents obtained with Mex and its tetramethyl-pyrroline derivatives [102].