Local Anesthetics Drugs Design---The Conformational Study of Biphenyl Anesthetics Drugs with Their Receptor Site in Transmembrane Segments of Voltage-Gate Na+ Channel by NMR & Molec

Local anesthetic drugs are clinical drugs that block the voltage-gated Na+ channels and hence stop the propagation of action potentials. In addition, many anesthetic drugs have been reported to slow dramatically the rate of recovery from inactivated Na+ channels. Therefore, understanding the molecular mechanism of local anesthetics and the interactions of these drugs with Na+ channel inactivation are of considerable physiological and pharmacological importance. Evidence from receptor mapping of local anesthetics within the multiple S6 segments, along with information regarding functional changes after the binding of the ligands, clearly indicates the important structural/functional roles of these S6 receptors. For rational drug design, the S6 segments will be fruitful targets, as they may govern proper Na+ channel functions in vivo. The interaction between local anesthetics and the Na+ channel S6 segments should be interesting and pressing need to determine for therapeutic drugs for long-acting local anesthetics. To study the interactions of local anesthetic with S6 segments, biphenyl drugs such as phenytoin, diphenhydramine, and phenylbutazone etc. will be selected to interact with model peptides that their sequences correspond to the S6 segments within domains I and IV of rat brain type IIA Na+ channel. The NMR spectroscopy and molecular modeling will be applied in this research proposal to closely look at the detail orientation of biphenyl groups in desirable structures of selected drugs, and study the effect of structural and conformational properties related to inhibition of inactivated Na+ channel. Further molecular modeling will be performed to identify possible inhibitor-receptor interactions that may be critical for recognition and signal transduction of inactivated Na+ channel. Such an approach, in principle, provides the information to determine the three dimensional biologically active conformation for the drug molecules, which in turn can lead to a fundamental understanding of drug』s recognition, and information transduction in the ligand-receptor systems. The results obtained from this study may provide alternative medications that produce safe, effective and non-addicting analgesic pharmaceuticals.

Project ID:PC9308-2059
External Project ID:NSC93-2320-B182-039