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Voltage-Dependent Sodium Channel Blocker Anticonvulsants: An Approach to the Structure-Activity Relationship

Author(s):

M. del Carmen Salazar-López, J. Alberto Guevara-Salazar*, Mónica G. Arellano-Mendoza, Hugo A. Jiménez-Vázquez, Adriana Benavides and Delia Quintana-Zavala   Pages 1 - 23 ( 23 )

Abstract:


Anticonvulsants are drugs used in the treatment of seizures, their pharmacology includes promoters of brain inhibition and inhibitors of brain activity; Of the latter, voltage-dependent sodium channel blockers (VGSCB) are the most widely used in therapeutics.

Objective: To propose the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity.

Methods: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico.

Results: Relationships were found between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisoster derivatives) and Group 2 (homologue and vinylogue derivatives of urea).

Conclusion: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.

Keywords:

Anticonvulsants, voltage-gated sodium channel blockers, SAR, QSAR, IC50, pharmacophore

Affiliation:

Departamento de Farmacología. Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, S/N, 11340, México, D.F, Departamento de Farmacología. Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, S/N, 11340, México, D.F, Laboratorio de Enfermedades Crónico-Degenerativas y Sección de Estudios de Posgrado e Investigación. Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México, D.F, Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala, 11340, México, D.F, Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación Manuel Carpio y Plan de Ayala, 11340, México, D.F, Laboratorio de Química Orgánica, Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada, Unidad Legaria, Instituto Politécnico Nacional, Legaria No. 694, 11500, México, D.F



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