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. 2013 Jan 22;104(2):344-54.
doi: 10.1016/j.bpj.2012.11.3830.

Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels

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Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels

Michela De Bellis et al. Biophys J. .

Abstract

Previously identified potent and/or use-dependent mexiletine (Mex) analogs were used as template for the rational design of new Na(v)-channel blockers. The effects of the novel analogs were tested on sodium currents of native myofibers. Data and molecular modeling show that increasing basicity and optimal alkyl chain length enhance use-dependent block. This was demonstrated by replacing the amino group with a more basic guanidine one while maintaining a proper distance between positive charge and aromatic ring (Me13) or with homologs having the chirality center nearby the amino group or the aromatic ring. Accordingly, a phenyl group on the asymmetric center in the homologated alkyl chain (Me12), leads to a further increase of use-dependent behavior versus the phenyl Mex derivative Me4. A fluorine atom in paraposition and one ortho-methyl group on the xylyloxy ring (Me15) increase potency and stereoselectivity versus Me4. Charge delocalization and greater flexibility of Me15 may increase its affinity for Tyr residues influencing steric drug interaction with the primary Phe residue of the binding site. Me12 and Me15 show limited selectivity against Na(v)-isoforms, possibly due to the highly conserved binding site on Na(v). To our knowledge, the new compounds are the most potent Mex-like Na(v) blockers obtained to date and deserve further investigation.

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Figures

Figure 1
Figure 1
Chemical structure of Mex and its newly synthesized analogs. The boxes show the compounds presently tested (continuous lines). Indicates the position of the chiral carbon atom.
Figure 2
Figure 2
Evaluation of the tonic and use-dependent block exerted by analogs S-Me4, S-Me12, and R-Me15. Upper panel A: are showing traces of INa transients recorded in the absence and presence of drug. In each group of traces, the greatest one has been recorded in the absence of drug, with a depolarizing step from the HP of −100 to −20 mV for10 ms. A similar depolarizing stimulus applied after the application of each compound allowed to estimate the TB exerted by the drug (middle traces). The smallest current traces correspond to the residual current at the end of the 10-Hz stimulation protocol. The INa reduction exerted by increasing drug concentrations and evaluated on the first-pulse trace and on the residual steady-state current allowed to construct the dose-response curves for TB and UDB at 10-Hz (lower panel B). Lower panel C: are showing concentration-response curves for TB and 10-Hz UDB of Na+ currents obtained with enantiomers of Me4 and Me15. The curves fitting the experimental points were obtained using the logistic function described in Materials and Methods. Each value is the mean ± SE from 4 to 8 fibers of the percent block of INa observed in the presence of each concentration of drugs versus INa in the absence of the drug in the same fiber.
Figure 3
Figure 3
(A) The two most stable conformers of Me15—a, synclinal, and b, synperiplanar; dihedral angles between the aromatic ring and ether functional group containing planes are highlighted. (B) Newman projections obtained observing a and b from the fluorine atom side in the direction of the bond connecting the latter to the aryloxy ring (for the sake of simplicity hydrogen atoms have been omitted). (C) Electrostatic potential maps for R-Me15 and R-Me4.

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