Our long-term objective is to develop drugs for the symptomatic treatment of peripheral neuropathies. Peripheral neuropathies are a diverse group of diseases (or syndromes) affecting a large population. Focal demyelination is known to occur in neuropathies, like Guillain-Barre Syndrome and Charcot-Marie-Tooth disease type l, resulting in delayed or blocked nerve conduction. Voltage-activated potassium channels normally do not play a significant role in mammalian axonal nerve conduction. However, demyelination leads to the exposure of paranodal potassium channels which dissipate the action potential by clamping the axon to the potassium equilibrium potential resulting in blocked nerve conduction. Blocking potassium channels exposed by demyelination provides an opportunity for symptomatic treatment. A high-throughput assay based on 96-well plate format has been established to screen an in-house library of 1700 compounds. using CHO cells stably expressing kv 1.1 channels.
Our specific aims are to identify compounds that: 1) are potent in blocking Kv 1.1 channels, 2) exhibit a margin of safety in cardio-vascular tests, 3) can restore nerve conduction in an animal model of acute-demyelination by lysophosphatidyl choline, and 4) are poorly permeable through blood-brain- barrier. Such compounds will be considered for development as therapeutic agents.
Potassium channel blockers have commercial potential as important new pharmacological agents for clinical indications that are characterized by abnormal axonal conduction of nerve impulses. This project will lead to the development of small molecule therapeutics capable of improving motor and sensory function in patients suffering from peripheral neuropathies secondary to diabetes (an estimated 1 - 6.7 million cases as of 1991), chemotherapeutic treatment of Cancer (approximately 260,000 new cases/year). movement-related neuropathies and primary demyelinating diseases such as chronic inflammatory demyelinating polyradiculoneuropathy.
