TRPV3 in Drug Development

Abstract

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.

Keywords: Olmsted syndrome; TRPV3; itch; keratinocytes; pain.

Figure 1

Total publications per year around TRPV3 (orange bars) relative to other thermo-TRPs (TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1). Data as of 25/05/2016. Searches were conducted using PubMed and, where applicable, included alternative nomenclature (e.g., TRPV1 and VR1).

Figure 2

Membrane topology of TRPV3. Residues involved in heat activation (N643, I644, N647, L658 and Y661), activation by 2-APB (H426 and R696), Camphor (C612 and C619) and modulation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂; R696 and K705), ATP (K169 and K174), Mg²⁺ (D641) and Ca²⁺ (R696) are highlighted, in addition to the location of ankyrin repeats [7,8,9,10,11,12,13].

Figure 3

Activators, inhibitors and modulators of TRPV3. Quaternary structure of TRPV3 with compounds and signalling pathways known to activate, inhibit or modulate the receptor. See Introduction for references–additional references [23,24,25,26].

Figure 4

Summary of TRPV3 expression and function in epidermal keratinocytes. TRPV3 protein has been found throughout the epidermis and around hair follicles, with protein elevated under certain inflammatory skin conditions.

Figure 5

Structure of TRPV3 selective antagonist FTP-THQ [63].

Figure 6

FTP-THQ [1-({[3-fluoro-5-(trifluoromethyl)pyridine-2-yl]sulfanyl}acetyl)-8-methyl-1,2,3,4-tetrahydroquinoline], a potent and selective TRPV3 receptor antagonist blocked TRPV3 mediated release of ATP (A & B) and GM-CSF (C) from mouse keratinocytes in vitro. Results are mean ± SEM of 3 independent experiments. Statistical significance was assessed using the paired Student’s t-test, * p < 0.05, ** p < 0.001.

Figure 7

Effects of FTP-THQ on histamine-induced scratching behavior. Harlan CD-1 mice (n = 7–8/treatment group), 4–5 weeks old were acclimated to testing room for 1 h. FTP-THQ was administered at 30, 100, or 200 mg/kg i.p., 1 h prior to histamine, while diphenhyramine was administered at 20 mg/kg, 30 min prior to histamine. Animals were then placed inside a clear plexiglass chamber and the number of scratching bouts was scored for 20 min. Data were collected via Abacus software; one-way ANOVA with post-hoc Dunnett’s was used for analysis. * p < 0.05 vs. vehicle control.

Figure 8

Effects of FTP-THQ on formalin-induced nocifensive behavior. Harlan Sprague Dawley Rats (n = 7–8/treatment group), were acclimated to the testing room for 1 h. FTP-THQ was administered at 50, 100, or 200 mg/kg i.p. 15 min prior to formalin, while the positive control tramadol was administered at 40 mg/kg i.p. 30 min prior to formalin. The animals were placed in Startle Behavior Chambers and behavior events (licking, guarding, flinching) binned in 5-min intervals and plotted as Early and Late Phase. Data were analyzed using 1-way ANOVA, and comparisons of drug treatment groups were compared with control groups using a post-hoc Dunnett’s comparison. * p < 0.05 vs. vehicle control.

Figure 9

Timeline of major TRPV3 development activities.

Figure 10

Number of patents applied for and granted per year for each of the thermo-TRPs compared to TRPV3 (orange bars).

Figure 11

Examples of patented TRPV3 antagonists from Glenmark Pharmaceuticals.

Figure 12

Representatives from Hydra Biosciences patented TRPV3 antagonist series.

Figure 13

A leading representative from Abbvie’s TRPV3 antagonist series.