In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold?

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.

Keywords: calcium channel; calcium signalling; cationic channel; ion channel inhibitors; sodium channel.

Figure 1

Expression and functions of TRPCs. On the left is a simple schematic diagram of a TRPC heteromer conferring influx of Ca²⁺ and Na⁺. In the middle is a list of the cell types that have been suggested to express TRPC mRNA or protein. On the right (in red) is a list of cell or whole tissue/body effects that have been suggested to be driven or potentiated by TRPC activity; in other words, if TRPC channels were to be inhibited, the opposite of the effect is predicted to occur (e.g. less pancreatitis). Example references for cell expression items: acinar gland cells (Liu et al., 2007); adipocytes (Sukumar et al., 2012); astrocytes (Shirakawa et al., 2010); cardiac myocytes (Eder and Molkentin, 2011); cochlea hair cells (Quick et al., 2012); endothelial cells (Ahmmed et al., 2004); epithelial cells (Kim et al., 2011); fibroblasts (Xu et al., 2008); hepatocytes (Rychkov and Barritt, 2011); keratinocytes (Cai et al., 2006); leukocytes (Yildirim et al., 2012); mast cells (Freichel et al., 2012); mesangial cells (Sours et al., 2006); neurones (Bollimuntha et al., 2011); osteoclasts/blasts (Abed et al., 2009); platelets (Ramanathan et al., 2012); podocytes (Dryer and Reiser, 2010); skeletal muscle (Gervasio et al., 2008); smooth muscle cells (Beech et al., 2004); and tumour cells (Thebault et al., 2006). Example references for effect items: angiogenesis (Yu et al., 2010); cancer cell drug resistance (Ma et al., 2012); cell adhesion (Smedlund et al., 2010); cell migration (Xu et al., 2006); cell proliferation (Sweeney et al., 2002); cell survival (Selvaraj et al., 2012); cell turning (Wang and Poo, 2005); efferocytosis (Tano et al., 2011); gastrointestinal motility (Tsvilovskyy et al., 2009); glomerular filtration (Dryer and Reiser, 2010); hypo-adiponectinaemia (Sukumar et al., 2012); hypo-matrix metalloproteinase (Xu et al., 2008); hypertrophy (cardiac) (Eder and Molkentin, 2011); innate fear (Riccio et al., 2009); lung hyper-responsiveness (Yildirim et al., 2012); mast cell degranulation (Ma et al., 2008); motor coordination (Trebak, 2010); muscle endurance (Zanou et al., 2010); neointimal hyperplasia (Kumar et al., 2006); oedema (Weissmann et al., 2012); permeability (Tiruppathi et al., 2002); pancreatitis (Kim et al., 2011); saliva secretion (Liu et al., 2007); seizure (Phelan et al., 2013); survival after MI (myocardial infarction) (Jung et al., 2011); thrombosis (Ramanathan et al., 2012); vaso-modulation (e.g. vasoconstriction) (Weissmann et al., 2006); and wound-healing (Davis et al., 2012).

Figure 2

Hyperforin and diacylphloroglucinol-based TRPC6 stimulators. The functionalized acylphloroglucinol core of hyperforin has been highlighted in red to indicate the structural similarities between hyperforin and the Hyp compounds. The diacylated phloroglucinol cores of the Hyp compounds are highlighted in blue. See the main text for details and references.

Figure 3

Structures of isoflavone- and thiazolidinedione-based TRPC stimulators. Red indicates the isoflavone core. Blue indicates the thiazolidinedione core. See the main text for details and references.

Figure 4

Structures of pyrazole-based TRPC inhibitors 12–17 and target identification probes 18 and 19. Blue indicates the similarities between the Pyr cores. Red indicates the distinguishing sulfonamide moiety of 17. See the main text for details and references.

Figure 5

Structures of 2-aminoquinoline-based TRPC inhibitors 20–31. Blue indicates the 2-aminoquinoline scaffold the inhibitors have in common. See the main text for details and references.

Figure 6

Structures of steroid-based TRPC inhibitors 32–37. Blue indicates the common steroid cores, whereas red indicates minor deviations from this core such as alternative bond oxidation states and substituents. See the main text for details and references.

Figure 7

Structures of phenylethylimidazole-based TRPC inhibitors 38–40. Blue indicates the structural elements that the scaffolds of the compounds have in common, whereas red indicates deviations from this scaffold. See the main text for details and references.

Figure 8

Structures of the Sigma-1-receptor ligands and TRPC5 inhibitors 41–43, and proposed pharmacophore 44. Lowest energy conformations of six-membered rings were drawn to emphasize structural similarities. Compounds 41 and 43 were used as their commercially available di-HBr salts. See the main text for details and references.

Figure 9

Structures of naphthalene sulfonamide-based TRPC inhibitors 45–48. Blue indicates the common naphthalene sulfonamide core, whereas red indicates the alternative position for naphthalene substitution in 48. See the main text for details and references.

Figure 10

Structures of N-phenylanthranilic acids and analogues 49–54. Blue indicates the N-phenylanthranilic acid scaffold, whereas red indicates deviations from this scaffold. See the main text for details and references.

Figure 11

Structures of ω-3 fatty acid inhibitors of TRPC channels, 55–57. See the main text for details and references.

Figure 12

Structures of the anti-oxidant gallic acid and trans-stilbene-based TRPC5 inhibitors, 58–60. See the main text for details and references.

Figure 13

General structure of putative TRPC3 and/or TRPC6 inhibitors in a GSK patent (61) and specific examples of potent inhibitors mentioned in the patent 62–65. See the main text for details and reference.

Figure 14

Structures of miscellaneous TRPC inhibitors, 66–79. See the main text for details and references.