Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC50 of 1.56 ± 0.13 μM. The maximum efficacy of CPIPC (30 μM) was about 60% of saturated capsaicin (10 μM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC. Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.

Graphene Loaded ZrO2 Nanocomposite for Antioxidant, Dye Removal, Electrochemical and Green Sensor Studies

“…The determination of the optical band gap involves plotting (hυ) versus (F(R)hυ) 2 , and at the inflection point, drawing a tangent to (F(R)hυ) 2 =0. As illustrated in Figure 1 (inset) (a), (b), and (c), the band gaps for rGO, ZrO 2 , and ZrO 2 /rGO are found to be 1.29, 1.45, and 1.26 eV, respectively [30] …”

Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching

“…The neck and head of compound 2 (Figure 7a) bind to R557. Gao et al (2016) and Dong et al (2022) confirmed that R557 is one of the key residues for the formation of agonism, which explains the agonism of compound 2 . The kind of partial agonist that acts antagonistically to high concentrations of capsaicin has been less studied and has only been similarly reported in vitamin D (Long et al, 2020).…”

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

“…The ligand-dependent cation channel TRPV1 is a promising target for managing various types of pain disorders [3]. In recent years, an increasing number of studies have focused on discovering TRPV1 antagonists and agonists/desensitizers as therapeutic solutions for chronic, neuropathic and inflammatory pain, but also for migraine and cluster headache [8,19,60]. Unfortunately, the approval of TRPV1 antagonists is hindered due to severe side effects observed in clinical trials, such as hyperthermia.…”