Molecular Dissection of Lubeluzole Use-dependent Block of Voltage-gated Sodium Channels Discloses New Therapeutic Potentials.
OPEN Molecular pharmacology | 24 Nov 2012
JF Desaphy, R Carbonara, T Costanza, G Lentini, MM Cavalluzzi, C Bruno, C Franchini and D Conte Camerino
Lubeluzole, which acts on various targets in vitro, including voltage-gated sodium channels (NaChs), was initially proposed as neuroprotectant. Lubeluzole structure contains a benzothiazole moiety (R-like) related to riluzole and a phenoxy-propranol-amine moiety (A-core) recalling propranolol. Both riluzole and propranolol are efficient NaCh blockers. We studied in detail the effects of lubeluzole (racemic mixture and single isomers), aforementioned lubeluzole moieties, and riluzole on NaChs to increase our knowledge about drug-channel molecular interactions. Compounds were tested on hNav1.4 NaChs, and F1586C or Y1593C mutants functionally expressed in HEK293 cells, using patch-clamp. Lubeluzole blocked NaChs with a remarkable effectiveness. No stereoselectivity was found. Compared to mexiletine, dissociation constant for inactivated channels was ≈600 times lower (≈11 nM), conferring to lubeluzole a huge use-dependence of great therapeutic value. The F1586C mutation impaired use-dependent block only partially, suggesting that additional amino acids are critically involved in high-affinity binding. Lubeluzole moieties were modest NaCh blockers. Riluzole blocked NaChs efficiently but lacked use-dependence, similarly to R-like. F1586C fully abolished A-core use-dependence, suggesting that A-core binds to the local anesthetic receptor. Thus lubeluzole likely binds to the local anesthetic receptor through its phenoxy-propranol-amine moiety, with consequent use-dependent behavior. Nevertheless, compared to other known NaCh blockers, lubeluzole adds a third pharmacophoric point through its benzothiazole moiety, that greatly enhances high-affinity binding and use-dependent block. If sufficient isoform specificity can be attained, the huge use-dependent block may help in the development of new NaCh inhibitors to provide pharmacotherapy for membrane excitability disorders, such as myotonia, epilepsy, or chronic pain.
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