Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators)

Kv1.1 channels are expressed in many regions of the brain and spinal cord [Monaghan, M. M.; Trimmer, J. S.; Rhodes, K. J. J. Neurosci. 2001, 21, 5973; Rasband, M. N.; Trimmer, J. S. J Comp. Neurol. 2001, 429, 166; Trimmer, J. S.; Rhodes, K. J. Ann. Rev. Physiol. 2004, 66, 477]. When expressed alone, they produce a delayed rectifier slowly inactivating type current that contributes to hyperpolarizing the neuron following depolarization. In the hippocampus Kv 1.1 is co-expressed with Kv beta 1 (and other P subunits), which converts Kv1.1 into a transient, fast inactivating current, reducing its ability to hyperpolarize the cell and thus increasing neuronal excitability. To reduce neuronal excitability, screening for compounds that prevent inactivation of Kv1.1 channels by Kv beta 1 was performed using a yeast two-hybrid screen. A variety of compounds were discovered in this assay and subsequently determined to disrupt inactivation of the ionic currents, and hence were termed 'disinactivators'. Several of these disinactivators also inhibited pentylenetetrazole-induced seizures (PTZ) in mice. Compounds were found to act by several mechanisms to prevent Kv beta 1 inactivation of Kv1.1 channels, including enhancement of Ca2+ release/influx and by direct mechanisms. Two structural classes were identified that act on a Kv beta 1N70-Kv1.1 chimera where the N-terminal 70 amino acids of Kv beta 1 were attached to the N-terminus of Kv1.1. It is likely that these disinactivators act directly on the Kv beta 1 N-terminus or its receptor site on Kv1.1, thus preventing it from blocking Kv1.1 channels. Compounds acting by this mechanism may be useful for reducing neuronal hyperexcitability in diseases such as epilepsy and neuropathic pain. (C) 2007 Elsevier Ltd. All rights reserved.