RESUMEN
A comprehensive comparative molecular field analysis (CoMFA) model for the binding of ligands to the neuronal voltage-gated sodium channel was generated based on 67 diverse compounds. Earlier published CoMFA models for this target provided µM ligands, but the improved model described here provided structurally novel compounds with low nM IC50. For example, new compounds 94 and 95 had IC50 values of 129 and 119 nM, respectively.
Asunto(s)
Relación Estructura-Actividad Cuantitativa , Canales de Sodio Activados por Voltaje/química , Ligandos , Modelos MolecularesRESUMEN
We previously developed a preliminary 3-D QSAR model for the binding of 14 hydantoins to the neuronal voltage-gated sodium channel; this model was successful in designing an effective non-hydantoin ligand. To further understand structural features that result in optimum binding, here we synthesized a variety of compound classes and evaluated their binding affinities to the neuronal voltage-gated sodium channel using the [3H]-batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) binding assay. In order to understand the importance of the hydantoin ring for good sodium channel binding, related non-hydantoins such as hydroxy amides, oxazolidinediones, hydroxy acids, and amino acids were included. Two major conclusions were drawn: (1) The hydantoin ring is not critical for compounds with long alkyl side chains, but it is important for compounds with shorter side chains. (2) Relative to Khodorov's pharmacophore, which contains two hydrophobic regions, a third hydrophobic region may enhance binding to provide nanomolar inhibitors.
Asunto(s)
Hidantoínas/síntesis química , Activación del Canal Iónico , Canales de Sodio/metabolismo , Animales , Corteza Cerebral/metabolismo , Hidantoínas/química , Hidantoínas/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Ligandos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Ensayo de Unión Radioligante , Ratas , Sinaptosomas/metabolismoRESUMEN
A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.