Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

“…Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated nonselective cation channel and member of the vanilloid TRP family. In the chromosome 17p13 is located the Trpv1 gene, which encodes a 95-kDa protein containing 839 amino acid residues [364]. TRPV1 has six transmembrane domains (TM), presenting a pore region located between TM5 and TM6 domains.…”

“…TRPV1 has six transmembrane domains (TM), presenting a pore region located between TM5 and TM6 domains. The N-terminal tail allows binding of calmodulin and ATP to modulate TRPV1 activation while C-terminus contains a TRP domain and binding sites for phosphatidylinositol 4,5-bisphosphate (PIP2) and calmodulin [364].…”

“…TRPV1 was first reported in sensory neurons of the dorsal root ganglion, nodose ganglia and trigeminal ganglia [364]. In the brain, it is found in regions of the hypothalamus, cerebellum, cerebral cortex, striatum, midbrain, hippocampus and substantia nigra [371].…”

Antioxidant Profile of Pepper (Capsicum annuum L.) Fruits Containing Diverse Levels of Capsaicinoids

“…From a pharmacological perspective, the research carried out so far has shown that capsaicinoids, particularly capsaicin, have a diversity of biological and physiological functions in vitro, so they play roles as antioxidants, stimulants of the energetic metabolism, fat accumulating suppressors, anti-inflammatories, neurostimulants and apoptosis-alleviating agents in neurodegenerative disorders [ 20 , 28 , 29 , 30 ]. Regarding the mechanism of action, capsaicinoids act on a family of ion channels known as transient receptor potential (TRP) channels which, in mammals, are framed within the subtype TRP Vanilloid (TRPV1) [ 31 , 32 ]. It has been also found that in many types of cancers, the proapoptotic activity of capsaicin is also mediated by this TRPV, and the activation of the p53 tumor suppressing protein by a phosphorylation process is induced by capsaicin [ 33 , 34 ].…”

Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs

“…It is well-established that selective sensory neuropathy can be induced by systemic capsaicin-induced desensitization. Systemic capsaicin treatment at appropriate doses induces a selective impairment of C-fiber primary sensory neurons expressing the capsaicin receptor TRPV1 [99,100,101]; which can be observed by, e.g., depletion of cardiac CGRP-containing afferent nerves [11]. Systemic capsaicin-desensitized animals have elevated chemical and heat pain thresholds, show no signs of pain, irritation or discomfort, and behave similar to controls [102].…”