Abstract

Previously identified potent and/or use-dependent mexiletine (Mex) analogs were used as template for the rational design of new Nav-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 Nav-isoforms, possibly due to the highly conserved binding site on Nav. To our knowledge, the new compounds are the most potent Mex-like Nav blockers obtained to date and deserve further investigation.

Autore Pugliese

• Carocci Alessia , De Luca Annamaria , Franchini Carlo , Lentini Giovanni , Desaphy Jean Francois , Cavalluzzi Maria Maddalena , De Bellis Michela

Tutti gli autori

• CAROCCI A.;DE LUCA A.;FRANCHINI C.;CONTE D.;LENTINI G.;DESAPHY J.F.;CAVALLUZZI M.M.;DE BELLIS M.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2013

ISSN

0006-3495

ISBN

Non Disponibile

Numero di citazioni Wos

13

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

15

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile