63002-09-5Relevant academic research and scientific papers
Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands
Zha, Congxiang,Brown, George B.,Brouillette, Wayne J.
, p. 6519 - 6528 (2007/10/03)
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-α-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.
Block of human NaV 1.5 sodium channels by novel α-hydroxyphenylamide analogues of phenytoin
Lenkowski, Paul W.,Ko, Seong-Hoon,Anderson, James D.,Brown, Milton L.,Patel, Manoj K.
, p. 635 - 644 (2007/10/03)
Voltage-gated sodium (Na) channels are a critical component of electrically excitable cells. Phenytoin (diphenylhydantoin, DPH) is an established sodium channel blocker and is a useful anticonvulsant and class 1b antiarrhythmic, and has been effectively used in the treatment of neuropathic pain. In this study, we have synthesized novel α-hydroxyphenylamide analogues of diphenylhydantoin and examined their ability to inhibit human Nav1.5 sodium channels expressed in Chinese Hamster Ovary (CHO-K1) cells. Phenyl ring substitutions were examined including para-methyl, para-fluoro, para-chloro, ortho-chloro and meta-chloro. We have found that phenyl ring substitutions with electron withdrawing properties resulted in compounds with greater activity. In comparison to diphenylhydantoin, the novel chloro-substituted α-hydroxyphenylamide compounds produced as much as a 20-fold greater tonic and frequency-dependent blockade of Nav1.5 channels with an IC50 value of 14.5μM. In addition, the chloro-substitutions have position specific state dependent blocking properties. The ortho-, meta- and para-chloro substitutions have an 8-, 13- and 3-fold increased affinity for the inactivated state, respectively. Molecular modeling suggests that these differences in affinity are due to a direct interaction with the receptor. Comparing models of diphenylhydantoin to the novel α-hydroxyphenlyamide compound suggests that the increased activity may be due to an optimized phenyl ring position and increased molecular volume. This information may be useful in the development of more potent sodium channel blockers.
Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel
Brown, Milton L.,Zha, Congxiang C.,Van Dyke, Christopher C.,Brown, George B.,Brouillette, Wayne J.
, p. 1537 - 1545 (2007/10/03)
Comparative molecular field analysis (CoMFA), a 3-D QSAR technique, is widely used to correlate biological activity with observed differences in steric and electrostatic fields. In this study, CoMFA was employed to generate a model, based upon 14 structur
