4-Aminopyridine

Voltage-gated K⁺ channels (K_V) play an important role in a number of different aspects of electrical responses of the nervous system. Their activity determines the frequency of action potentials and the shape of the action potential waveform. Furthermore, K_V channels may regulate the excitability of individual neurons and may control the strength of synaptic contacts between neurons^1,2.

4-Aminopyridine (4-AP) is a non-selective K_V channel blocker³, which can block a wide variety of K_V channels with different state dependencies⁴. Therefore, in search for clues for the structural determinants of K_V channels that are important for the state dependencies of drug-channel interactions, 4-AP serves as a useful tool. For example, it blocks K_V2.1 and K_V3.1 channels with IC₅₀s of 18 and 0.1 mM, respectively, in oocytes⁵. K_V1.1 and K_V1.2 channels are blocked by 4-AP with IC₅₀s of 147 µM and 230 µM, respectively, in CHO cells³.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterized by axonal conduction block⁶. 4-AP has been tested as a symptomatic treatment in patients with MS based on the clinical rationale that neurological function could be improved by overcoming conduction block in demyelinated axons present in MS lesions. Indeed, 4-AP restored conduction in experimentally demyelinated nerves in the peripheral nervous system⁷. In addition, 4-AP increased presynaptic action potential duration and amplitude leading to enhanced transmitter release⁸.