Voltage-gated ion channels play important roles in a variety of biological processes, and the availability of potent and selective modulators of these channels has facilitated understanding of their roles in health and disease.  T-type calcium channel antagonists are low-voltage activated ion channels implicated in a number of conditions such as epilepsy, pain, sleep disorders, tremor, and schizophrenia.  While a number of compounds have been reported to inhibit T-type calcium channels such as ethosuximide, mibefradil, and pimozide, their activity at a number of different receptors and ion channels precludes conclusive determination of the consequences of T-type calcium channel inhibition.  This presentation will describe the identification and optimization of several different structural classes of T-type calcium channel antagonists for increased potency, selectivity and brain penetration.  Evaluation of optimized compounds in epilepsy, pain, sleep, and schizophrenia models will be described.  The consistent biological results from each of the different classes of compound tested in the same animal models give confidence that the observed effects are due to T-type calcium channels inhibition, and suggest that these compounds could be useful in a variety of neurological disorders.

Exploring chemical neuroscience with T-type calcium channel antagonists

243rd National Meeting (2012)

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