Abstract
The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.
Highlights
Introduction to the pharmacology ofTransient Receptor Potential Canonical (TRPC) channelsThere are few, if any, established small molecules or toxins that are highly selective and potent modulators of TRPC channels, and there are no published crystal structures on462 British Journal of Pharmacology (2013) 170 459–474 which the design of modulators can be based
The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7)
Important progress has been made in recent years towards the identification of selective and potent small molecule modulators of TRPC channels
Summary
Pyr in this series (12 in Figure 4) is recognized as an inhibitor of Ca2+ entry induced by store depletion and it may be this effect that leads to suppression of NFAT (Zitt et al, 2004; He et al, 2005). Pyr (13, Figure 3) is suggested to inhibit TRPC3 relatively selectively (Table 1). In addition to showing selectivity within the TRPC subgroup (Table 1), Pyr fails to inhibit TRPM2, TRPM4 or TRPM7 channels (Kiyonaka et al, 2009). Structural similarities of Pyr and Pyr-PP to the other five Pyr compounds, in combination with inhibition data, strongly suggest that these compounds may be direct TRPC3 binders. Pyr was found to inhibit Orai channels, and so, the compound may not be as specific for TRPC3 as is widely suggested. It should be noted that unbiased analysis of Jurkat T cell lysates with probe BTP-biotin (19) suggested binding to the actin
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