Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of N-indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure–activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively. The whole-cell clamp patch assay shows that 28 is a potent and selective TRPV1 agonist and it relieves inflammatory and thermal pain by desensitizing the native TRPV1 current in the dorsal root ganglion (DRG) in mice. Additionally, site-directed mutagenesis combined with molecular docking shows an important hydrogen interaction between Arg557 and the indazole of 28. Taken together, our findings provide insight into TRPV1 agonism–antagonism conversion based on the interaction between indazole and Arg557, which provides a strategy to obtain new TRPV1 agonists by structural modification of antagonists. Compound 28 may be used as a lead compound for further optimization.

Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

“…To understand this intriguing observation and facilitate the design of more potent modulators, molecular docking of TRPV1‐ligand interaction indicates R557 interacts with the indazole through a critical hydrogen bond. Thus, the indazole scaffold is suitable for further optimization [90] …”

Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance

“…Abdominal and back pain is a very common and unbearable symptom for pancreatic cancer patients that current therapies fail to manage satisfactorily, heavily affecting patients’ quality of life. Some receptors belonging to the endocannabinoidome, particularly TRPV1, located in pancreatic cancer cells and tissues, CB1 and CB2, GPR55, GPR199 and PPAR-α, have been found to be involved in pain regulation [ 96 , 97 , 98 , 99 ]. Therefore, using cannabinoids to target these receptors could perform a dual function by not only counteracting cancer progression, but also by being a valid course of action to alleviate the burden of pain in pancreatic cancer.…”

Introducing Bis(5-(Trifluoromethyl)pyridin-2-yl)amine Chelating Unit via Pd-Catalyzed Amination

“…On the other hand, pyridine and other heterocycles can form complexes with palladium and interfere with the reaction, which may require careful optimization of the catalytic system [23,24]. Amination of commercially available 2-bromo-5-(trifluoromethyl)pyridine under Cu-, Ni-and Pd-catalyzed conditions was previously reported [25][26][27][28][29][30], but only a few examples of Pd-catalyzed N,N-diarylation of amines with this substrate are reported. Thus, N,N-diarylation of aliphatic amines is described for two examples [26].…”