Editorial [Hot Topic: Membrane Channels as Therapeutic Targets (Executive Editor: Jean-Claude Herve)]

The production of new molecular entities endowed with salutary medicinal properties is a formidable challenge that involve several steps and requests rational target identification, recognition and avoidance of adverse properties of therapeutics before commitment to clinical trials, monitoring of clinical efficacy using surrogate markers and individualized approaches to disease treatment. The first to face up to is the initial identification and selection of macromolecular targets upon which de novo drug discovery programs can be initiated. A drug target needs to answer several criteria (as known biological function(s), robust assay systems for in vitro characterisation and high-throughput screening) and to be specifically modified by and accessible to small molecular weight compounds in vivo. Membrane channels have many of these attributes and can be viewed as suitable targets for small molecule drugs. Membrane channels are allosteric proteins that open and close a permeable pore (a process called gating), allowing ions and sometimes small molecules to flow across the cell membrane in a regulated manner. Their gating can be regulated by various stimuli including changes in membrane voltage, binding of extracellular or intracellular ligands, membrane stretch, enzymes and G-proteins. They play critical roles in a broad range of physiological processes, including electrical signal transduction, chemical signalling (involving different second messengers), transepithelial transport, regulation of cytoplasmic or vesicular ion concentration and pH, as well as regulation of cell volume. Channel dysfunction may lead to a number of diseases termed channelopathies, and a number of common diseases (e.g. epilepsy, hypertension, arrhythmia, chronic pain or type II diabetes) are primarily treated by drugs that modulate ion channel activities. The cell-based methods for evaluating membrane channel pharmacology are based on several distinct techniques such as electrophysiology, fluorescence, radioligand binding or displacement, and radiotracer flux assays. A better understanding of membrane channel structures and of channel functions has been achieved in recent years by three main scientific advances, the patch-clamp technique, the use of selective neurotoxins and the cloning and sequencing of genes. They allowed to investigate the pharmacological effects of traditional (antiarrhythmic, antiepileptic, ...) drugs and the development of new approaches. This issue of Current Pharmaceutical Design, the third of four parts, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these channels. A wide range of neurotransmitters, polypeptides and inflammatory mediators transduce their signals into the interior of cells by specific interactions with cell-surface receptors that are coupled to G-protein. Muscarinic acetylcholine receptors, one of the most familiar of them, mediate transmission of acetylcholine to neuronal or effector cells. There are five subtypes of closely homologous muscarinic receptors which are coupled by means of heterotrimeric G-proteins to a variety of signalling pathways resulting in a multitude of target cell effects. Masaru Ishii and Yoshihisa Kurachi [1] review the latest advances in the structural and functional characterization of these receptors and the pharmaceutical development of muscarinic receptor ligands. Glutamate is regarded as the most widespread excitatory neurotransmitter in the mammalian brain. Two classes of glutamate receptors have been cloned, the ionotropic (ligand-gated ion channels) and the metabotropic (G protein-coupled receptors). Ionotropic glutamate receptors mediate basic information processing in the brain and induce changes in synaptic efficacy, but their functional realm has been found to extend well outside the central nervous system to include roles in insulin secretion, bone resorption, cardiac pacemaking, as well as involvement in taste and tactile sensation. Rosa Planells-Cases, Juan Lerma and Antonio Ferrer-Montiel [2] overview the current knowledge available concerning the pharmacology of these channels. Cyclic nucleotide-gated ion channels are non-selective cation channels that are opened by the direct binding of intracellular cyclic nucleotides and behave as molecular amplifiers, with large changes in activity resulting from small changes in cyclic nucleotide concentration. Taking advantage of emerging structural information and the increasing knowledge of the biophysical properties of these channels, some promising compounds and strategies have begun to emerge. Lane Brown, Timothy Strassmaier, James Brady and Jeffrey Karpen [3] discuss progress on two fronts, cyclic nucleotide analogues as both activators and competitive inhibitors, and inhibitors that target the pore or gating machinery of the channel. Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1 to 5-HT7)....