Potassium channel openers as potential therapeutic weapons in ion channel disease

The opening of potassium (K+) channels, causing hyperpolarization of the ce ll membrane. is a physiological means of decreasing cell excitability. Thus , drugs with this property 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 ch annel openers" was initially associated with a group of chemically diverse agents (for example. cromakalim, pinacidil, nicorandil) that evoke K+ efflu x through adenosine 5'-triphosphate (ATP)-sensitive K+ channels (K-ATP). Th is finding initiated a search to identify molecules that specifically open other K+ channel subtypes (for example large conductance calcium-activated K+ channels [BKCa]). K+ channel opening properties have been demonstrated i n a diverse range of synthetic chemical structures and endogenous substance s. Second generation K-ATP channel openers (KATPCOs) demonstrate heterogene ous pharmacology indicative of independent sites of action for the differen t agents. Successful cloning of the K-ATP channel has shed light on the het erogeneity of the structure targeted by KATPCOs. Expression of the actions of KATPCOs involves three isoforms of the sulfonylurea (SUR) receptor (whic h forms the beta subunit of the K-ATP channel). The distribution of the SUR isoforms (and potential of identifying new isoforms) provides unique targe ts for the development of selective KATPCOs giving focused therapeutic appr oaches to clinical conditions for example cardiac ischemia, urinary inconti nance, neurodegeneration, obesity and autoimmune diseases. BKCa channels ar e 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 mole cules (for example, NS004. fenamates) and natural product derived compounds (DHS-I, maxikdiol) have been identified as selective BKCa channel openers which should have a profound impact in controlling diseases. The discovery of numerous variants of the or subunit lion conductance pore) and beta subu nit (contributes biophysical and pharmacological properties) complex of the BKCa channel gives potential to target specific tissues with selective ope ners. Little is known, however, about the site(s) Of interaction of openers of these channels. The discovery of K+ channel subtype-specific openers an d their evaluation in different diseases will determine the: degree to whic h these channels (K-ATP, BKCa), or their isoforms, represent realistic ther apeutic targets. Drugs already marketed that open K+ channels were discover ed empirically, and most have serious safety and efficacy problems. New sci entific methods, utilizing molecular insight are implicating K+ channel dys function in numerous disease states and art identifying new targets for the future generation of K+ channel opening drugs.