title: Searching for novel anti-myotonic agents: pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide.
abstract: Drug screening on sodium currents of native myofibers by means of voltage-clamp recordings is predictive of pre-clinical anti-myotonic activity in vivo and ex vivo. By this approach we identified the N-benzylated beta-proline derivative of tocainide (To10) as the most potent use-dependent blocker of Nav1.4 so far. We tested novel analogs with modifications on the pharmacophore groups of To10. The substitution of the proline cycle with less planar piperidine or piperazine rings disclosed the importance of a two carbon atom distance and/or an additional nitrogen atom for potency. Structural changes on the xylididic group corroborated the role of a proper electronic cloud for hydrophobic interactions with the binding site. The N-benzylated moiety lead to a stereoselective behavior only in the rigid alpha-proline analog To11 vs. To10 and N-benzylated tocainide (To12). The results confirm the strict structural requirements of Nav1.4 blockers and allow to refine the drug design toward novel anti-myotonic drugs.
authors.affiliation: Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Aldo Moro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.forename: Filomena
authors.initials: F
authors.lastname: Corbo
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.forename: Marilena
authors.initials: M
authors.lastname: Muraglia
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.forename: Diana Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000818:Animals; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011392:Proline / Q000737:chemistry; D011893:Rana esculenta; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship; D016677:Tocainide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016677:Tocainide; D011392:Proline