Voltage-Gated Ion Channel-Targeted Library

ChemDiv’s library of small molecules targeting voltage-gated ion channels contains 5,000 chemically diverse compounds. 

Voltage-gated ion channels were among the first types of ion channels to be identified. These channels possess specific sequence motifs essential for their targeting, as these sequences may mediate interactions with proteins directly or indirectly involved in channel binding. Voltage-gated ion channels are either composed of a single α-subunit that forms a contiguous polypeptide containing four repeated domains (I–IV), or they are made up of four separate α-subunits, each contributing a single domain [1]. Sodium channels, a type of voltage-gated ion channel, remain closed and inactive at rest but undergo structural changes in response to membrane depolarization. This leads to the channel cycling through activated (open), inactive, and repriming states.

Pain perception is a complex process that depends on electrical activity within sensory neurons. In these neurons, voltage-gated sodium channels play a crucial role in generating and conducting action potentials. This fundamental role of sodium channels in electrogenesis has made them attractive targets for pharmacotherapeutic interventions aimed at reducing neuronal firing that leads to pain. Research has indicated that specific sodium channel isoforms are significant contributors to chronic pain. Sodium channels can be modulated by various small molecule pharmacological agents. Many clinically relevant modulators, such as lidocaine and carbamazepine, demonstrate pronounced state-dependent binding. This means that sodium channels that are rapidly and repeatedly activated and inactivated are more susceptible to blockade [2].

Voltage-gated ion channels play a crucial role in pharmacology and cynical therapy, serving as key targets for a wide range of therapeutic interventions due to their fundamental involvement in cellular electrical signaling. These channels, which open or close in response to changes in membrane potential, are essential in the propagation of action potentials in nerve and muscle cells. As such, they are critical in regulating essential physiological processes, including muscle contraction, hormone secretion, and neuronal communication.  In pharmacotherapy, these channels are targeted to treat an array of conditions, from cardiac arrhythmias and epilepsy to chronic pain and psychiatric disorders. Drugs that modulate the activity of these channels, such as calcium channel blockers for hypertension or sodium channel blockers for neuropathic pain, work by altering ion flow through the channels, thereby adjusting cellular excitability and physiological responses. The specificity and widespread presence of voltage-gated ion channels in the body make them highly attractive and versatile targets for therapeutic drug development.

The development of voltage-gated ion channel blockers is a well-established area of drug discovery because of their ability to modulate key physiological functions affected in various diseases. These blockers are invaluable in creating highly targeted treatments, offering the potential for fewer side effects compared to drugs with broader mechanisms of action. Moreover, the discovery of novel ion channel blockers has opened new therapeutic avenues, particularly for diseases with limited treatment options, enhancing patient care and outcomes. Their role in addressing unmet medical needs, especially in neurology and cardiology, underscores their significance in advancing medical science and therapy. Our library serves as a source of novel pharmacophores for innovative drug discovery of novel agents blocking voltage-gated channels.

References

[1] H. C. Lai and L. Y. Jan, “The distribution and targeting of neuronal voltage-gated ion channels,” Nat. Rev. Neurosci., vol. 7, no. 7, pp. 548–562, 2006, doi: 10.1038/nrn1938.

[2] S. D. Dib-Hajj, J. A. Black, and S. G. Waxman, “Voltage-gated sodium channels: Therapeutic targets for pain,” Pain Med., vol. 10, no. 7, pp. 1260–1269, 2009, doi: 10.1111/j.1526-4637.2009.00719.x.