martes, 12 de agosto de 2014

Canales de sodio/Sodium channels

El canal de sodio como diana de los anestésico locales

The sodium channel as a target for local anesthetic drugs.
Fozzard HA, Sheets MF, Hanck DA.
Front Pharmacol. 2011 Nov 1;2:68. doi: 10.3389/fphar.2011.00068. eCollection 2011.
Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA), which have been used for local and regional anesthesia and for excitatory problems such as epilepsy and cardiac arrhythmia. These drugs are prototypes for new analgesic drugs. The drug-binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated) position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development.
KEYWORDS:Na channel; gating currents; lidocaine; local anesthetics; molecular modeling

Progresos recientes en moduladores del canal de sodio para el dolor

Recent progress in sodium channel modulators for pain.
Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA.
Bioorg Med Chem Lett. 2014 Jun 21. pii: S0960-894X(14)00666-0. doi: 10.1016/j.bmcl.2014.06.038. [Epub ahead of print]
Voltage-gated sodium channels (Navs) are an important family of transmembrane ion channel proteins and Nav drug discovery is an exciting field. Pharmaceutical investment in Navs for pain therapeutics has expanded exponentially due to genetic data such as SCN10A mutations and an improved ability to establish an effective screen sequence for example IonWorks Barracuda®, Synchropatch® and Qube®. Moreover, emerging clinical data (AZD-3161, XEN402, CNV1014802, PF-05089771, PF-04531083) combined with recent breakthroughs in Nav structural biology pave the way for a future of fruitful prospective Nav drug discovery.

Anestesiología y Medicina del Dolor
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