Efficacy of ABT-116, an antagonist of transient receptor potential vanilloid type 1, in providing analgesia for dogs with chemically induced synovitis

Cathcart, Curtis J.; Johnston, Spencer A.; Al‐Nadaf, Sami; Budsberg, Steven C.

doi:10.2460/ajvr.73.1.19

Cited by 16 publications

(23 citation statements)

References 39 publications

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“…Indeed, a variant of TRPV1 has been associated to a reduced risk of pain in OA . All together, these data support an important role for TRPV1 antagonists to relieve OA pain, even though two of them, ABT‐116 and AZD1386, failed to give significant pain relief in this pathology . Furthermore, we have to consider that OA is a complex pathology where TRPV1 is only one pain target …”

Section: Pathophysiological Rolesmentioning

confidence: 79%

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

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

128

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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.

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Section: Pathophysiological Rolesmentioning

confidence: 79%

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

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

128

View full text Add to dashboard Cite

show abstract

“…Consisitent with these findings, in a randomized, double‐blinded, prospective clinical trial with client‐owned dogs suffering from severe hip osteoarthritic pain, the TRPV1 antagonist ABT‐116 showed only marginal analgesic activity over placebo (Malek et al ., ). ABT‐116 did not attenuate lameness in dogs with experimentally induced urate synovitis either at doses at which it caused seriously high rectal temperatures (Cathcart et al ., ). The striking difference in the analgesic activity of TRPV1 antagonists between rodent (where it potently reduces experimental osteoarthritic pain; Honore et al ., ; Puttfarcken et al ., ) and canine (without clinical benefits, see earlier) models of human osteoarthritic pain is puzzling and concerning.…”

Section: Pain and Trp Channelsmentioning

confidence: 97%

Transient receptor potential (TRP) channels: a clinical perspective

Kaneko

Szállaśi

2014

British J Pharmacology

333

259

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Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field. LINKED ARTICLESThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx

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“…Taken together, these findings identify TRPV1 as a promising target to relieve OA pain. However, the TRPV1 antagonist -4-(trifluoromethyl)phenyl)methyl)-N9-(1-methyl-1H-indazol-4-yl)] did not provide any significant pain relief in dogs with experimental synovitis (Cathcart et al, 2012) or naturally occurring, age-related hip OA (Malek et al, 2012), and AZD1386 (Fig. 9) was withdrawn from clinical trials in patients with OA after a periodic review of the data failed to show any clinical benefit (Svensson et al, 2010;Miller et al, 2014).…”

Section: Transient Receptor Potential Channels: Acquired Diseasesmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

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Efficacy of ABT-116, an antagonist of transient receptor potential vanilloid type 1, in providing analgesia for dogs with chemically induced synovitis

Abstract: HDA had no apparent effect on sodium urate-induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern.

Cited by 16 publications

References 39 publications

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

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

Transient receptor potential (TRP) channels: a clinical perspective

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

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