Small-conductance calcium activated potassium channels are encoded by the KCa2.1-2.3 (= SK1-3) genes and are best known for underlying the apamin-sensitive medium afterhyperpolarization current (mAHP) in neurons. Depending on the type of neuron, the function of KCa2 channels varies from determining instantaneous firing rates, over setting tonic firing frequencies, to regulating burst firing and potentially catecholamine release. Pharmacological modulation of KCa channels therefore offers the opportunity to significantly affect neuronal excitability. While KCa2 channel blockers like the bee venom apamin increase firing rates and induce seizures in rodents, KCa2 channel activators slow down neuronal firing and have therefore been proposed for the treatment of CNS disorders that are characterized by hyperexcitability such as epilepsy, ataxia, and neuropathic pain. However, this compelling therapeutic hypothesis currently remains largely untested because none of the existing KCa2 channel activators such as EBIO (EC50 300 μM) or NS309 are suitable for in vivo use. Using the neuroprotective drug riluzole as a synthetic template, our laboratory recently designed SKA-31 (EC50 2 uM), the first KCa2 channel activator, which is potent enough to be used in vivo, and demonstrated in collaboration with the NIH Anticonvulsant Screening Program (ASP) that the compound and several of its derivatives are effective anticonvulsants. Unfortunately, SKA-31 also activates KCa3.1 channels, which are expressed on vascular endothelium, and thus reduces blood pressure in mice. Using a combination of classical medicinal chemistry and automated and manual electrophysiology we intend to further explore the structure activity relationship around SKA 31 and EBIO in order to improve selectivity for KCa2 over KCa3.1 as well as potency and brain penetration. The best new KCa2 activators will then be evaluated for selectivity over a panel of cloned ion channels and characterized for activity on native KCa2 channels using hippocampal slices. Compounds selectively activating cloned and native KCa2 channels will further be evaluated for pharmacokinetic properties and brain penetration in rats using HPLC/MS. In parallel, we will submit selected compounds to the ASP, where the compounds will we tested in acute seizure models. Promising compounds will then be tested in amygdala kindled mice and rats with kainate-induced epilepsy, two models that are more representative of human refractory epilepsy. The design of brain penetrant and potentially subtype selective KCa2 channel activators would help to validate KCa2 channels as novel pharmacological targets for the treatment of epilepsy and would further provide the scientific community with tool compounds to study the role of KCa2 channels in ataxia, neuropathic pain and cognition.

Public Health Relevance

Project Narrative KCa2 potassium channels play important roles in determining neuronal excitability. Activators of these channels have therefore been suggested as new therapeutics for the treatment of diseases that are characterized by neuronal hyperexcitability such as epilepsy and ataxia. With the help of this grant we will attempt to design a KCa2 channel activator that is potent and selective enough to be used as a scientific tool compound or even to be developed into a drug.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-C (58))
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Farkas, Rebecca M
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University of California Davis
Schools of Medicine
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Mishra, Ramesh C; Mitchell, Jamie R; Gibbons-Kroeker, Carol et al. (2016) A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model. Vascul Pharmacol 79:24-31
Oliván-Viguera, Aida; Valero, Marta Sofía; Coleman, Nicole et al. (2015) A novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits endothelium-derived hyperpolarization-type relaxation in coronary artery and produces bradycardia in vivo. Mol Pharmacol 87:338-48
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Mishra, Ramesh C; Wulff, Heike; Hill, Michael A et al. (2015) Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels. J Cardiovasc Pharmacol 66:118-27
Coleman, Nichole; Nguyen, Hai M; Cao, Zhengyu et al. (2015) The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed KCa2 activator and NaV blocker, is a potent novel anticonvulsant. Neurotherapeutics 12:234-49
Coleman, Nichole; Brown, Brandon M; Oliván-Viguera, Aida et al. (2014) New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Mol Pharmacol 86:342-57
Mishra, Ramesh C; Wulff, Heike; Cole, William C et al. (2014) A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats. J Mol Cell Cardiol 72:364-73
Olivan-Viguera, Aida; Valero, Marta Sofia; Murillo, Maria Divina et al. (2013) Novel phenolic inhibitors of small/intermediate-conductance Caýýýýý-activated Kýýý channels, KCa3.1 and KCa2.3. PLoS One 8:e58614
Wulff, Heike; Kohler, Ralf (2013) Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. J Cardiovasc Pharmacol 61:102-12
Lam, Jenny; Coleman, Nichole; Garing, April Lourdes A et al. (2013) The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases. Expert Opin Ther Targets 17:1203-20

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