Transient Receptor Potential Channels As Therapeutic Targets
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REVIEWS Transient receptor potential channels as therapeutic targets Magdalene M. Moran*, Michael Allen McAlexander‡, Tamás Bíró§ and Arpad Szallasi||¶ Abstract | Transient receptor potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights potential opportunities for therapeutic intervention. Transient receptor potential (TRP) channels (BOX 1; FIG. 1) second messenger signalling cascades that are initiated are being ardently pursued as targets for drug discovery. by receptor activation, and some TRP channels function There are several factors that make TRP cation channels on intracellular membranes3. appealing as drug targets. First, although ion channels TRP channels are associated with several pathophysi- have been successful drug targets, achieving subtype- ological processes, which include (but are not limited to) selectivity has always been a major challenge, particu- pain, respiratory reflex hypersensitivity, cardiac hyper- larly with voltage-gated sodium and calcium channels. trophy and ischaemic cell death3. In addition, several As members of the TRP family of channels do not share gene association studies in humans have indicated that much homology with one another, the identification of single-nucleotide polymorphisms (SNPs) in the cod- subtype-selective compounds is likely to be more attain- ing regions and/or promoters of genes that encode TRP *Hydra Biosciences, able. Second, TRP channels act as integrators of several channels are either associated with an increased risk of 790 Memorial Drive, well-described signalling systems, including those that multifactorial diseases or they appear to be causative Cambridge, Massachusetts are mediated by cell surface receptors (for example, factors in rare heritable conditions4. Interestingly, when 02139, USA. G protein-coupled receptors (GPCRs) and growth fac- these mutated TRP channels are expressed in recombi- ‡Neuronal Targets Discovery Performance Unit, tor receptors). Third, mutations in many of the genes nant systems, they generally display enhanced activity, GlaxoSmithKline that encode TRP channels are sufficient to cause disease which suggests that blockade of these channels may pro- Pharmaceuticals,King of in humans. vide therapeutic benefit. Prussia, Pennsylvania, USA. Pioneering research in the field of pain has established To date, target validation of TRP channels has largely § Department of Physiology, that a subset of TRP channels (those that are activated been generated via genetic studies; by comparison, the Research Center for Molecular Medicine, by temperatures; the so-called thermoTRP channels) identification of chemical modulators of TRP channels University of Debrecen, 4032 are capable of initiating sensory nerve impulses fol- is in its infancy. Several natural ligands (for example, Debrecen, Hungary. lowing the detection of chemical and thermal stimuli capsaicin and menthol) have provided valuable insights ||Department of Pathology, (reviewed in REFS 1,2). Although pain is currently the into the pharmacology of TRP channels (reviewed in Monmouth Medical Center, REFS 1,2,5 300 Second Avenue, most advanced TRP channel-related field, an increasing ). Although these molecules can be informa- Long Branch, number of gene deletion studies in animals and genetic tive when they are used as tools for compound screen- New Jersey 07740, USA. association studies in humans have demonstrated that ing, they rarely display the potency, selectivity and/or ¶Drexel University College the pathophysiological roles of TRP channels extend well the physical properties that are desirable in modern of Medicine, Philadelphia, beyond the sensory nervous system (reviewed in REF. 3). drug discovery programmes. However, despite these Pennsylvania 19102, USA. Correspondence to A.S. Indeed, even broadly classifying TRP channels as sensors obstacles several pharmaceutical companies have been e‑mail: [email protected] of environmental cues understates the diversity of their able to develop blockers of TRP cation channel subfam- doi:10.1038/nrd3456 function. In fact, many TRP channels are activated by ily V, member 1 (TRPV1; also known as the capsaicin NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 601 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Pruritus receptor); these blockers have been sufficiently safe and developments in this rapidly evolving field, highlight Pruritus (also called an itch) is effective in preclinical studies to merit their testing in crucial advances and look ahead to the next steps in an unpleasant cutaneous clinical trials. Many of these trials are still underway elucidating the roles of TRP channels in neurology, der- sensation that is associated (TABLE 1; Supplementary information S1 (box)), but the matology, pulmonology, cardiology, urology, oncology with an urge to scratch. Various categories of pruritus have results of published trials have not been straightforward; and heritable diseases. been suggested, including rather, they have raised new questions regarding the role pruriceptive itch (which arises of TRPV1 in humans. TRP channels as analgesic targets from skin conditions), Despite these setbacks, we believe that the pace of The role of TRP channels is best understood in the pain neurogenic itch (which is drug discovery in the field of TRP channels has inten- area (FIG. 2). TRPV1 and TRPV3 antagonists have already caused by systemic disorders), (TABLE 1) neuropathic itch (which is due sified. The diversity in the expression, function and advanced to clinical trials , whereas TRPA1 to a primary neurological structure of TRP channels provides the opportunity antagonists (TABLE 2) are still in preclinical development. disorder) and psychogenic itch. to generate novel, selective chemical entities that can be tested in diverse clinical indications. Molecules that TRPV1. As the desensitization of nociceptive neurons to target TRPV3 have entered Phase I trials6 (see the Sanofi capsaicin has analgesic potential5, the cloning of the cap- website), and blockers of TRP cation channel subfamily saicin receptor, TRPV1 (REF. 9), has spurred considerable A, member 1 (TRPA1)6, TRP cation channel subfamily efforts in the pharmaceutical community to find TRPV1 M, member 8 (TRPM8)7 and TRPV4 (REF. 8) have been antagonists. However, side effects associated with the use efficacious in preclinical disease models and devoid of of TRPV1 antagonists have so far prevented any com- unexpected acute adverse effects that could limit their pounds from progressing beyond testing in Phase II tri- tolerability (TABLE 2). als. Particular concerns have surfaced around the effects Although results from clinical trials will serve as the of TRPV1 antagonism on the regulation of body tem- final arbiters of the utility of TRP channel modulators perature10 and in the detection of noxious heat (S. Eid, as therapeutics, current evidence indicates that these personal communication). channels contribute to the development and/or progres- sion of the symptoms of many diseases (for example, TRPV1 and regulation of body temperature. neuropathic pain, overactive bladder, asthma, anxiety Trpv1‑null9,11 and -knockdown12 mice have an appar- disorders and pruritus) and that they are therapeutic ently normal body temperature, despite the fact that they targets that are amenable to blockade by small mole- prefer lower ambient temperatures13. These characteris- cules. In this Review, we summarize the state-of-the-art tics are also observed in rats in which TRPV1‑expressing Box 1 | Introduction to TRP channels The transient receptor potential (TRP) cation channel superfamily is a diverse family of 28 cation channels that have varied physiological functions, including thermal sensation, chemosenation, magnesium transport and iron transport (reviewed in REF. 3). The TRP channel superfamily is classified into six related subfamilies: TRP cation channel subfamily C (canonical; TRPC), TRP cation channel subfamily V (vanilloid; TRPV), TRP cation channel subfamily M (melastatin; TRPM), TRP cation channel subfamily A (ankyrin; TRPA), TRP cation channel polycystin subfamily (TRPP) and TRP cation channel mucolipin subfamily (TRPML)3. The TRPML and TRPP subfamilies were named after the human diseases they are associated with (mucolipidosis and polycystic kidney disease, respectively). The founding member of the TRPM subfamily, TRPM1, was identified via comparative analysis of genes that distinguish benign nevi from malignant melanoma146. The TRPA subfamily has only one known member (TRPA1) and its name refers to the unusually high number of ankyrin repeats at the amino terminus of the channel protein (FIG. 1). Mammalian TRP channels that are most similar to the product of the Drosophila melanogaster Trp gene are referred to as TRPC proteins3. The TRPV subfamily was identified following expression cloning of TRPV1, which is the receptor for the prototypical irritant vanilloid, capsaicin9.