title: Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels.
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.
authors: Unit of Pharmacology, Department of Pharmacy-Drug Science, University of Bari, Aldo Moro, Italy.
authors: Michela
authors: M
authors: De Bellis
authors: Annamaria
authors: A
authors: De Luca
authors: Jean F
authors: JF
authors: Desaphy
authors: Roberta
authors: R
authors: Carbonara
authors: Judith A
authors: JA
authors: Heiny
authors: Ann
authors: A
authors: Kennedy
authors: Alessia
authors: A
authors: Carocci
authors: Maria M
authors: MM
authors: Cavalluzzi
authors: Giovanni
authors: G
authors: Lentini
authors: Carlo
authors: C
authors: Franchini
authors: Diana Conte
authors: DC
authors: Camerino
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008801:Mexiletine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers; D008801:Mexiletine