Targeting voltage-gated sodium channels for pain therapy.
Drugs inhibiting voltage-gated sodium channels have long been used as analgesics, beginning with the use of local anaesthetics for sensory blockade and then with the discovery that Nav-blocking anticonvulsants also have benefit for pain therapy. These drugs were discovered without knowledge of their molecular target, using traditional pharmacological methods, and their clinical utility is limited by relatively narrow therapeutic windows. Until recently, attempts to develop improved inhibitors using modern molecular-targeted screening approaches have met with limited success. However, in the last few years there has been renewed activity following the discovery of human Nav1.7 mutations that cause striking insensitivity to pain. Together with recent advances in the technologies required to prosecute ion channels as drug targets, this has led to significant progress being made. This article reviews these developments and summarises current findings with these emerging new Nav inhibitors, highlighting some of the unanswered questions and the challenges that remain before they can be developed for clinical use.
Clare
Jeffrey J
JJ
Cell-Based Assays Group, Millipore Corporation, St Charles, Missouri 63304, USA. jeff.clare@ntlworld.com
D000595:Amino Acid Sequence; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels