Potassium channel openers as potential therapeutic weapons in ion channel disease

Abstract

The opening of potassium (K+) channels, causing hyperpolarization of the cell membrane, is a physiological means of decreasing cell excitability. Thus, drugs with this properly will demonstrate a broad clinical potential. The identification of synthetic molecules that evoke physiological responses (for example smooth muscle relaxation) by the opening of K+ channels led to a new direction in the pharmacology of ion channels. The term 'potassium channel openers' was initially associated with a group of chemically diverse agents (for example, cromakalim, pinacidil, nicorandil) that evoke K+ efflux through adenosine 5'-triphosphate (ATP)-sensitive K+ channels (K(ATP)). This finding initiated a search to identify molecules that specifically open other K+ channel subtypes (for example large conductance calcium-activated K+ channels [BK(Ca)]). K+ channel opening properties have been demonstrated in a diverse range of synthetic chemical structures and endogenous substances. Second generation K(ATP) channel openers (K(ATP)COs) demonstrate heterogeneous pharmacology indicative of independent sites of action for the different agents. Successful cloning of the K(ATP) channel has shed light on the heterogeneity of the structure targeted by K(ATP)COs. Expression of the actions of K(ATP)COs involves three isoforms of the sulfonylurea (SUR) receptor (which forms the β subunit of the K(ATP) channel). The distribution of the SUR isoforms (and potential of identifying new isoforms) provides unique targets for the development of selective K(ATP)COs giving focused therapeutic approaches to clinical conditions for example cardiac ischemia, urinary incontinence, neurodegeneration, obesity and autoimmune diseases. BK(Ca) channels are found in a diverse array of tissues and due to voltage and Ca sensitivity may work as a negative feedback process. A variety of small synthetic molecules (for example, NS004, fenamates) and natural product-derived compounds (DHS-I, maxikdiol) have been identified as selective BK(Ca) channel openers which should have a profound impact in controlling diseases. The discovery of numerous variants of the α subunit (ion conductance pore) and β subunit (contributes biophysical and pharmacological properties) complex of the BK(Ca) channel gives potential to target specific tissues with selective openers. Little is known, however, about the site(s) of interaction of openers of these channels. The discovery of K+ channel subtype-specific openers and their evaluation in different diseases will determine the degree to which these channels (K(ATP), BK(Ca)), or their isoforms, represent realistic therapeutic targets. Drugs already marketed that open K+ channels were discovered empirically, and most have serious safety and efficacy problems. New scientific methods, utilizing molecular insight, are implicating K+ channel dysfunction in numerous disease states and are identifying new targets for the future generation of K+ channel opening drugs.