Blockers of Voltage-Gated Sodium Channels for the Treatment of Central Nervous System Diseases

Abstract

Voltage gated sodium channels play important roles both in vital physiological functions and several pathological processes of the central nervous system. Epilepsy, chronic pain, neurodegenerative diseases, and spasticity are all characterized by an over-excited state of specific groups of central neurons that is accompanied by an abnormally increased activity of sodium channels. An efficient strategy of controlling such diseases is to use blockers that preferentially act on these over-excited cells. State dependently acting agents, such as phenytoin, or lamotrigine, leave normal physiological functions relatively intact, resulting in a favorable therapeutic window. Nine isoforms of the channel forming alpha subunit are known, which show distinct expression patterns in different tissues. Another possible way to decrease the chance of adverse effects is to develop agents selectively inhibiting the channel subtype involved in the pathomechanism of the disease to be treated. Many recent patents claim sodium channel blockers with improved characteristics regarding state dependency or subtype selectivity. Such agents may offer a breakthrough in the treatment of a variety of central nervous system diseases. This review focuses on the current trends in sodium channel research, surveying the traditional and newly emerging therapeutic fields, and the diverse medicinal chemistry of sodium channel blockers.

Molecular Model of Anticonvulsant Drug Binding to the Voltage-Gated Sodium Channel Inner Pore

“…These molecules are wider and more rigid than local anesthetics. Although structurally different, anticonvulsant drugs interact with some of the same amino acid residues in the Na ϩ channel's inner pore and have similar overall open/inactivated state affinity (Ragsdale et al, 1996;Ragsdale and Avoli, 1998;Clare et al, 2000;Liu et al, 2003;Tarnawa et al, 2007). Most local anesthetic drugs with high affinity for the open/inactivated state are tertiary amines that are easily protonated at physiological pH, and the positive charge is thought to contribute importantly to their binding (Hille, 2001;McNulty et al, 2007;Ahern et al, 2008).…”

Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels

“…In the clinic this absence of subtype selectivity can result in toxicities associated with unwanted interactions with off-target Na v channels (e.g., cardiac toxicity due to inhibition of cardiac Na v 1.5 channels) (24,25). Therefore, because of their importance in normal physiology and pathophysiology, identification of selective pharmacological modulators of Na v channels is of considerable interest to the scientific and medical communities (9,23,(26)(27)(28)(29). For example, in addition to the therapeutic utility of sodium channel inhibitors described above, there has been recent interest in potentially targeting inhibition of specific Na v channel subtypes (i.e., Na v 1.7, Na v 1.8, and Na v 1.3) for the treatment of pain (9,(30)(31)(32).…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…Volted-gated sodium channels as drug targets in CNS disorders were recently deeply reviewed by Mantegazza et al [2], Chahine et al [3] and Tarnawa et al [4]. In the current review we would like to summarize up to date information regarding their use in CNS disorders.…”