Authors: Alice Weatherston
A study carried out by a team of researchers at the University of Pittsburgh (PA, USA), published recently in Molecular Pharmacology, has presented a novel version of retigabine that may help to reduce the side effects associated with the FDA-approved epilepsy drug.
Epilepsy drugs are often limited in their efficacy, with nearly a third of patients not responding to treatments. The development of novel, effective pharmacological treatments is therefore greatly in need.
Retigabine, although effective at reducing symptoms in some patients, can lead to adverse effects such as retinal abnormalities, skin discoloration and urinary retention.
The team at Pittsburgh, led by Thanos Tzounopoulos and Peter Wipf (both University of Pittsburgh) set out to rationally redesign a range of structural components of retigabine in order to increase its potency.
Primarily, drugs utilized in the treatment of epilepsy target the transport of chloride, sodium and potassium ions across the nerve cell membrane, in an effort to reduce excitation. Retigabine specifically, works by activating all five different types of potassium transport channels in the KCNQ category. Despite this, only two of these channels (KCNQ2/3) are actually important in controlling nerve cell hyperexcitability.
Importantly, the new compound developed by Tzounopoulos and Wipf, termed RL648_81, targets these channels only. “We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective,” commented Tzounopoulos.
Tzounopoulos was also part of a previous study team that initially developed an earlier modification of retigabine, termed SF0034, and is now being developed by SciFluor Life Sciences LLC (MA, USA).
In the current study, they consequently decided to directly compare retigabine, SF0034 and RL648_81 in laboratory tests. Results indicated that RL648_81 was 15 times more potent than retigabine and three times more potent than SF0034.
The team believe that in addition to its potential for increased efficacy, the specificity of RL648_81 will also help to reduce the side effects associated with the use of retigabine. They also hope to test the compound on other disorders caused by hyperexcitability of nerve cells, such as tinnitus.
“At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments,” commented Wipf. “RL-81 appears to have great potential for the treatment of these challenging neurological conditions.”