title: 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.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.affiliation: Section of Pharmacology, Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.affiliation: Section of Pharmacology, Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.affiliation: Section of Pharmacology, Department of Medical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D006801:Humans; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin
keywords: TRPV1 antagonists; medicinal chemistry; pathophysiology; structure-activity relationships; transient receptor potential vanilloid 1