A Genetically Validated Drug Target

Medicine has long known that blocking sodium channels will block pain.  This is exactly how local anesthetics, such as lidocaine and novocaine work.  However, these drugs also block other sensations, such as touch and pressure as well as the ability to contract muscles for movement.  These non-pain-specific effects are due to the lack of selectivity of local anesthetics.  There are actually nine types of voltage-gated sodium channels in the nervous system, which are named NaV1.1-NaV1.9 (Na = sodium; V = voltage gated).  

Over the past decade, voltage-gated sodium channel 1.7 (NaV1.7) has emerged as one of the most promising targets for novel pain therapeutics. Humans who are born with loss-of-function mutations in the gene encoding NaV1.7 cannot experience pain. Similarly, humans born with a gain-of-function mutation of the Nav1.7 gene experience increased pain states, including a horrific condition called termed paroxysmal extreme pain disorder.

Scientific studies revealed that NaV1.7 is required for initiation of pain signals. Therefore, a drug that selectively blocks the NaV1.7 channel has the potential to produce very strong analgesia for any kind of pain without the side effects associated with local anesthetics, opioids, or NSAIDs.  The only expected side effect of NaV1.7 blockade is diminished sense of smell - because this is the only function, other than pain, for which this channel seems to be critical. However, despite immense effort in the pharmaceutical industry, discovery of drugs that selectively switch off or block NaV1.7 in order to stop pain in human subjects has been difficult to achieve.

 

 

extracellular view of the nav 1.7 channel

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discovering selective nav 1.7 inhibitors has proven challenging