title: Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands.
abstract: 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.
authors.affiliation: Department of Chemistry, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Congxiang
authors.initials: C
authors.lastname: Zha
authors.forename: George B
authors.initials: GB
authors.lastname: Brown
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D006827:Hydantoins; D008024:Ligands; D015222:Sodium Channels