Patents related to therapeutic activation of K_ATP and K_2P potassium channels for neuroprotection: ischemic/hypoxic/anoxic injury and general anesthetics

Abstract

Background: Mechanisms of neuroprotection encompass energy deficits in brain arising from insufficient oxygen and glucose levels following respiratory failure; ischemia or stroke, which produce metabolic stresses that lead to unconsciousness and seizures; and the effects of general anesthetics. Foremost among those K⁺ channels viewed as important for neuroprotection are ATP-sensitive (K_ATP) channels, which belong to the family of inwardly rectifying K⁺ channels (K_ir) and contain a sulfonylurea subunit (SUR1 or SUR2) combined with either K_ir6.1 (KCNJ8) or K_ir6.2 (KCNJ11) channel pore-forming α-subunits, and various members of the tandem two-pore or background (K_2P) K⁺ channel family, including K_2P1.1 (KCNK1 or TWIK1), K_2P2.1 (KCNK2 or TREK/TREK1), K_2P3.1 (KCNK3 or TASK), K_2P4.1 (KCNK4 or TRAAK), and K_2P10.1 (KCNK10 or TREK2). Objectives: This review covers patents and patent applications related to inventions of therapeutics, compound screening methods and diagnostics, including K_ATP channel openers and blockers, as well as K_ATP and K_2P nucleic/amino acid sequences and proteins, vectors, transformed cells and transgenic animals. Although the focus of this patent review is on brain and neuroprotection, patents covering inventions of K_ATP channel openers for cardioprotection, diabetes mellitus and obesity, where relevant, are addressed. Results/conclusions: Overall, an important emerging therapeutic mechanism underlying neuroprotection is activation/opening of K_ATP and K_2P channels. To this end substantial progress has been made in identifying and patenting agents that target K_ATP channels. However, current K_2P channels patents encompass compound screening and diagnostics methodo-logies, reflecting an earlier ‘discovery’ stage (target identification/validation) than K_ATP in the drug development pipeline; this reveals a wide-open field for the discovery and development of K_2P-targeting compounds.

Keywords::

• ATP-sensitive potassium channels
• ischemia
• K_2P
• K_ATP
• local anesthetics
• neuroprotection
• tandem two-pore potassium channels