Chloride channel opener

Ion Channels Ion channels are pore-forming proteins which help facilitate the transport of ions across membranes, typically plasma membranes or the membranes of organelles within cells [14]. They are considered to be the second largest drug target for existing drugs, after G protein-coupled receptors. Such transport channels, including ligand gated and voltage gated channels, regulate uptake of chemical stimulants that trigger neuronal function. as well as Sodium (Na+) and Potassium (K+), determine the electrochemical potential across a cell. In the central nervous system (CNS), chloride channels are responsible for both direct modulation of neuronal activity and indirect control of neuronal functions through release of gliotransmitters by astrocytes through gating of organic anions such as GABA. Groups are assigned by molecular properties and variance in activation stimuli. CLC channel proteins, which are expressed on cell membranes, organelles, and vesicles, are of particular interest for the development of chloride channel openers due to their regulation of chloride ion transport and gradients for many cellular functions. Expressed as either anion channels or anion/protein exchangers, these proteins can join to form homomeric or heteromeric dimers. This so-called "double-barreled" structure poses both a potential for new understanding and very complex drug design utilizing the surprising structure of the ClC-1 protein. The CFTR channels are therefore critical to determining transepithelial salt transport, fluid flow, and concentrations of ions. CFTR chloride channels have important roles in various aspects of the human body, such as in fluid and electrolyte secretion within the intestines, pancreas, and sweat glands. The structure of the CFTR consists of five domains: two nucleotide-binding domains, two membrane-spanning domains, and a single regulatory domain. CaCCs are activated by cytosolic calcium ions, and moderate transmembrane anion transport in response to an increase in the intracellular concentration of calcium ions. The most notable CaCC is formed by TMEM16A, which is present in several tissues of the body. TMEM16A has a variety of different functions within the various tissues it is present in, such as in chloride ion secretion with the airway epithelia, making it an important target for the development of chloride modulating drugs which treat cystic fibrosis. At lower transmembrane potentials, VDAC channels are more selective for anions such as chloride ions, as opposed to cations, but at higher transmembrane potentials, they favor cations over anions. Both GABA-A and GABA–C receptors are ionotropic ligand-gated chloride channels, while the GABA-B receptor is a G-protein-linked metabotropic receptor. The ionotropic GABA-A and GABA-C receptors can be activated by GABA to open and allow entry of negatively chloride ions into a cell, playing a significant role in the control of neuronal excitability. As a result, both GABA-A and GABA-C receptors, particularly GABA-A receptors, represent prominent targets for the development of chloride channel agonist drugs. GABA-A receptor inhibition GABA-A receptors are GABA-gated anion channels which are involved in the function of rapid inhibitory synaptic transmission through the vertebrate CNS [28]. These receptors are coupled with intrinsic chloride channels that are triggered to open through the binding of GABA, which is an inhibitory neurotransmitter. When activated, GABAergic inhibition of two types, phasic and tonic, will occur. Phasic GABA-A receptor-mediated inhibition is a result of a brief exposure of postsynaptic GABA-A receptors to high concentrations of GABA. Alternatively, tonic GABA-A receptor-mediated inhibition results from an activation of extrasynaptic receptors by low concentrations of ambient GABA. Somewhere between 75% and 90% of GABA-A inhibition in the CNS is tonic. GABA-A receptor structure and disease GABA-A receptors are part of the cys-loop pentameric ligand-gated ion channel family, which includes multiple neurotransmitter-gated channels. GABAA receptors are assembled from five subunits. Such subunits and splice variants can be distinguished as α1-α6, β1-β3, γ1-γ3, δ, ε, π and θ. GABA-A receptor subunit mutations are believed to be a potential cause for many neurological and CNS disorders. For example, epilepsy related sleep disturbances are believed to be partially caused by improper activation of the β3 GABA-A receptor subunit. Various other pathological mood disorders including anxiety and schizophrenia are major therapeutic targets for GABA-A. GABA-A therapeutics are a related therapy that could potentially be treated or targeted by chloride ion channel opener drugs. Perception of chloride ion gated channels as drug targets Chloride channels were largely overlooked as drug targets for many years with a greater emphasis placed on ligand gated channels due to the high selectivity (easy targeting) of ligands in comparison to chloride ions. Outside of the discovery of the GABA-A receptors, chloride channels have remained understudied in the world of drug therapeutics. The discovery of GABA-A receptors has allowed the scientific community to see that chloride channels could have a direct link to central nervous system (CNS) cell operation. However, the lack of a complete understanding of the precise workings of chloride channels hinders the creation of drugs which can modulate these channels with a high level of specificity. == Channel Modulators Overview ==

Channel Modulators Channel modulating drugs, otherwise known as ion channel modulators, belong to a category of drugs which control the operation of ion channels. Channel modulators can act as either blockers or openers of these channels, and can either directly or indirectly modulate ion channels. Ion channel modulation is of great significance in drug development, as ion channel modulators can be used to treat a wide variety of medical conditions, including diabetes and hypertension. Targeting Ion Channels Ion channels are significant drug targets due to their importance in a vast range of physiological processes. However, the development of ion channel modulating drugs has historically been challenging due to certain factors such target specificity, structural complexity of ion channel proteins, identification of drug binding sites, and the drug screening methods. Regarding specificity, as ion channels have a variety of different functions, a lack of selectivity can cause undesirable side effects from channel modulators. Mechanism of Action There are a variety of factors that contribute to the activation of chloride channels. Some of the factors contributing to CLC activation would be cellular swelling, chloride imbalance, intracellular Ca2+ signaling, membrane potential changes, and intracellular pH changes, among others. One example of a common chloride channel activator which is used to treat both constipation caused by IBS (irritable bowel syndrome) as well as cystic fibrosis would be Lubiprostone. This drug is poorly absorbed following oral administration, until its eventual metabolization within the stomach and the small intestine (specifically the jejunum). After it is metabolized, Lubiprostone utilizes membrane stimulation to selectively stimulate CLC-2 (type 2 chloride channels) channels leading to a pathway that releases fluids, relieving symptoms. Another example would be the drug ivermectin which binds to glutamate-gated chloride channel receptors, triggering them to open and allow chloride ions to flow into a cell. Ivermectin binds in the transmembrane domain of the glutamate-gated chloride channel receptors, allowing for an open-pore conformation. Medical Use/Treatment The development of drug targets for anion gated channels such as chloride channels has lagged behind the development of cation gated channels due to technical challenges pertaining to the screening methods for chloride-channel modulators. == Applications ==

Treating genetic mutations which cause Cystic Fibrosis Chloride gated channel opener mutations have been a major pharmacologic target, as dysfunction of this receptor results in common muscular diseases such as hyperekplexia and even depressive disorders.[5]. A mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most common mutation causing cystic fibrosis and has, therefore, been a logical target for therapeutics. Multiple companies have created chloride channel targeting drugs with the intent of modulating/altering CLC-1 function, such as Acetazolamide (a drug that elevates chloride conductance, acting as a chloride channel opener) and NMD670, a CLC-1 inhibitor. CLC-2 is more commonly expressed in the CNS and thus contributes to a wide array of functions that can lead to disease states if mutated. In particular, CLC-2 mediates chloride currents and aids with blood flow and neuroprotection of the hippocampus. CLC-2 channel dimers have protopores that can be opened individually or together via a common gating process activated by hyperpolarization. Drugs such as Omeprazole and Lubistiprone seek to activate CLC-2 channels in specific areas utilizing their ability to be activated by methods such as extracellular pH shift. CLC-2 has also been linked to neurological diseases such as epilepsy. Treating Epilepsy As one of the most common neurological disorders, epilepsy is an advantageous target for treatment. It is believed that epilepsy is associated with extremely high levels of calcium, up to 2-5 times the normal physiological levels of calcium. Propositions have been made to utilize the relationship between extracellular and intracellular ions to regulate high and persistently high levels of calcium when applicable. Though this approach could, in theory, be a solution, the lack of success in studies targeting calcium channels for this expressed purpose have been mostly abandoned [27]. Thus, the likelihood of further investment in chloride ion channel openers as opposed to calcium ion channel openers is low without significant scientific discovery or innovation. == Future Perspectives ==

Future research on chloride channel opener drugs will likely involve the complete translation of chloride channel opener research from concept to incorporation into human medicine. While chloride channel openers, and modulators in general, are gaining traction as a promising treatment target for diseases such as cystic fibrosis, there are very few treatments that have progressed past animal models. Indeed, Lubistiprone (trade name: Amitiza) is one of the only commercially available uses of chloride channel openers in humans. One of the major issues preventing the development of not only chloride channel openers, but any channel modulators specifically targeting chloride channels would be the relatively poor understanding of certain aspects of chloride channels themselves. Although a vast range of information is available regarding chloride channel function and physiological roles, there are gaps in the present literature, such as the molecular identification of volume-sensitive chloride channels. Due to the diverse set of conditions that are linked to chloride channel proteins, there is great potential for future research into chloride channel openers for conditions outside of cystic fibrosis such as epilepsy and other neurological diseases affected by CLCs. == See also ==