Indole-2-Carboxamide As an Effective Scaffold for the Design of New TRPV1 Agonists

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2025 Feb 13

PMID 39942824

Authors

Samuele Maramai

Claudia Mugnaini

Marco Paolino

Aniello Schiano Moriello

Luciano De Petrocellis

Federico Corelli

Francesca Aiello

Antonella Brizzi

Affiliations

Soon will be listed here.

Abstract

Due to its central role in pain, inflammation, and related disorders, the Transient Receptor Potential (TPR) Vanilloid Type-1 (TRPV1) ion channel represents an attractive target for the development of novel antinociceptive and anti-inflammatory agents. Capsaicin, the natural component of chili peppers, is one of the most investigated agonists of this receptor. Several modifications of its structure have been attempted, aiming at finding TRPV1 agonists with improved characteristics, but, to date, no capsaicin-derived agents have reached the market. Based on our previous knowledge of the design and synthesis of TRPV1 agonists, in this paper we propose two small series of indole-2-carboxamides as novel and selective agonists for this ion channel. The newly developed compounds have been structurally characterized and tested in vitro for their ability to modulate TRPV1, in terms of efficacy, potency (EC), and desensitization (IC) properties. For the most promising derivatives, selectivity over the TRP ankyrin-1 (TRPA1) channel has been reported. From our study, compound arose as a promising candidate for further evaluation, also in correlation with its in silico-predicted drug-like properties.

References

Yang F, Zheng J . Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Protein Cell. 2017; 8(3):169-177. PMC: 5326624. DOI: 10.1007/s13238-016-0353-7. View

La Regina G, Silvestri R, Gatti V, Lavecchia A, Novellino E, Befani O . Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B. Bioorg Med Chem. 2008; 16(22):9729-40. DOI: 10.1016/j.bmc.2008.09.072. View

Moriello A, De Petrocellis L, Vitale R . Fluorescence-Based Assay for TRPV1 Channels. Methods Mol Biol. 2022; 2576:119-131. DOI: 10.1007/978-1-0716-2728-0_9. View

Bujak J, Kosmala D, Szopa I, Majchrzak K, Bednarczyk P . Inflammation, Cancer and Immunity-Implication of TRPV1 Channel. Front Oncol. 2019; 9:1087. PMC: 6805766. DOI: 10.3389/fonc.2019.01087. View

Saito S, Tominaga M . Evolutionary tuning of TRPA1 and TRPV1 thermal and chemical sensitivity in vertebrates. Temperature (Austin). 2017; 4(2):141-152. PMC: 5489018. DOI: 10.1080/23328940.2017.1315478. View

Maximiano T, Carneiro J, Fattori V, Verri W . TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain. Cell Calcium. 2024; 119:102870. DOI: 10.1016/j.ceca.2024.102870. View

Marrone M, Morabito A, Giustizieri M, Chiurchiu V, Leuti A, Mattioli M . TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat Commun. 2017; 8:15292. PMC: 5436240. DOI: 10.1038/ncomms15292. View

Chapa-Oliver A, Mejia-Teniente L . Capsaicin: From Plants to a Cancer-Suppressing Agent. Molecules. 2016; 21(8). PMC: 6274000. DOI: 10.3390/molecules21080931. View

Brizzi A, Aiello F, Marini P, Cascio M, Corelli F, Brizzi V . Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist. Bioorg Med Chem. 2014; 22(17):4770-83. DOI: 10.1016/j.bmc.2014.07.006. View

10.

Adetunji T, Olawale F, Olisah C, Adetunji A, Aremu A . Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer. Front Oncol. 2022; 12:908487. PMC: 9326111. DOI: 10.3389/fonc.2022.908487. View

11.

De Petrocellis L, Moriello A, Fontana G, Sacchetti A, Passarella D, Appendino G . Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels. Br J Pharmacol. 2013; 171(10):2608-20. PMC: 4009003. DOI: 10.1111/bph.12320. View

12.

Maharjan A, Vasamsetti B, Park J . A comprehensive review of capsaicin: Biosynthesis, industrial productions, processing to applications, and clinical uses. Heliyon. 2024; 10(21):e39721. PMC: 11543913. DOI: 10.1016/j.heliyon.2024.e39721. View

13.

Knotkova H, Pappagallo M, Szallasi A . Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?. Clin J Pain. 2008; 24(2):142-54. DOI: 10.1097/AJP.0b013e318158ed9e. View

14.

Nozadze I, Tsiklauri N, Gurtskaia G, Tsagareli M . Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats. Behav Pharmacol. 2015; 27(1):29-36. DOI: 10.1097/FBP.0000000000000176. View

15.

Brizzi A, Maramai S, Aiello F, Baratto M, Corelli F, Mugnaini C . Lipoic/Capsaicin-Related Amides: Synthesis and Biological Characterization of New TRPV1 Agonists Endowed with Protective Properties against Oxidative Stress. Int J Mol Sci. 2022; 23(21). PMC: 9658705. DOI: 10.3390/ijms232113580. View

16.

Alawi K, Keeble J . The paradoxical role of the transient receptor potential vanilloid 1 receptor in inflammation. Pharmacol Ther. 2009; 125(2):181-95. DOI: 10.1016/j.pharmthera.2009.10.005. View

17.

Chahl L . TRPV1 Channels in the Central Nervous System as Drug Targets. Pharmaceuticals (Basel). 2024; 17(6). PMC: 11206835. DOI: 10.3390/ph17060756. View

18.

Romeo I, Brizzi A, Pessina F, Ambrosio F, Aiello F, Belardo C . -Guided Rational Drug Design and Synthesis of Novel 4-(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists. J Med Chem. 2023; 66(10):6994-7015. DOI: 10.1021/acs.jmedchem.3c00447. View

19.

Aiello F, Badolato M, Pessina F, Sticozzi C, Maestrini V, Aldinucci C . Design and Synthesis of New Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channel Modulators: Identification, Molecular Modeling Analysis, and Pharmacological Characterization of the N-(4-Hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl)butanamide,.... ACS Chem Neurosci. 2016; 7(6):737-48. DOI: 10.1021/acschemneuro.5b00333. View

20.

Willis Jr W . The role of TRPV1 receptors in pain evoked by noxious thermal and chemical stimuli. Exp Brain Res. 2009; 196(1):5-11. DOI: 10.1007/s00221-009-1760-2. View