Vanilloid Receptor Antagonists: Emerging Class of Novel Anti-Inflammatory Agents for Pain Management

Abstract

Neuropathic pain affects 26 million patients worldwide resulting in a worldwide healthcare cost over $ 3 billion per year. Despite the availability of an impressive arsenal of powerful drugs for the effective management of pain, there remains a great medical need for new medicines to treat pain. While little is known about the proteins that detect noxious stimuli (especially those of a physical nature), vanilloid receptor, an excitatory ion channel expressed by nociceptors, has been identified as molecular target for the development of recent therapies to treat pain. Initially, the focus was on the development of TRPV1 agonists e.g. capsaicin and resiniferatoxin (RTX) as analgesic agents through the desensitization/denervation approach. While various formulations of capsaicin are either marketed or are currently under development, this approach is often hindered by the pain and discomfort experienced on initial treatment. Thus, TRPV1 antagonists are being evaluated as promising drug candidates to inhibit the transmission of nociceptive signals from the periphery to the CNS and to block other pathological states associated with this receptor. Since the discovery of capsazepine as the first TRPV1 antagonist, multiple classes of antagonists has been reported that can be broadly classified as urea/amide-based and non-urea/non-amide-based agents. However, depending on their chemical structures all these agents can be grouped as benzenesulfonamides, cinnamides, ureas, thio-ureas, amides, benzimidazoles, and piperazine carboxamides, N-aryl-cinnamides etc. The present review will focus on all these antagonists as an emerging class of novel, analgesic, antiinflammatory agents that have been reported in the literature over the last several years and the status of the developmental candidates in various stages of clinical trials.

Alkamid database: Chemistry, occurrence and functionality of plant N-alkylamides

“…spilanthol (1) (Rios et al, 2007), by interfering with voltage-gated sodium channels or via desensitization of the TRPV1 receptor. TRPV1 agonists initially stimulate sensory neurons and release of substance P, followed by a long-lasting refractory period, during which the previously excited neurons are no longer responsive to a broad range of stimuli (Bode and Dong, 2011;Luo et al, 2011;Pal et al, 2009). Therefore, prolonged ingestion or topical application of capsaicinoids can be successful in managing painful conditions such as rheumatoid arthritis, osteoarthritis, diabetic neuropathy, postherpetic, neuralgia, postmastectomy pain syndrome, cluster headache, reflex sympathetic dystrophy and gastro-intestinal related problems like reflux and functional dyspepsia (Holzer, 2011;Philip and Thakur, 2011).…”

Is an easy and reliable diagnosis of localized neuropathic pain (LNP) possible in general practice? Development of a screening tool based on IASP criteria

“…These clinical manifestations are relatively similar across the different neuropathic pain conditions 7 which may exhibit different combinations of signs and symptoms in several patients. The true prevalence of NP is difficult to estimate 5 , possibly affecting approximately 26 million patients worldwide 8 but particularly high among patients with diabetes (20.3%) 9 , cancer (10.8%) 10 , after surgical procedures (up to 50%) 11 , or following herpes zoster (8%) 12 . The annual NP incidence was evaluated at almost 1% of the general Dutch population 13 .…”

7-tert-Butyl-6-(4-Chloro-Phenyl)-2-Thioxo-2,3-Dihydro-1H-Pyrido[2,3-d]Pyrimidin-4-One, a Classic Polymodal Inhibitor of Transient Receptor Potential Vanilloid Type 1 with a Reduced Liability for Hyperthermia, Is Analgesic and Ameliorates Visceral Hypersensitivity

“…The role of TRPV1 in somatic inflammatory and neuropathic pain has been extensively characterized, with multiple TRPV1 inhibitors shown to be effective analgesics both clinically and preclinically in conditions with marked hyperalgesia (Szallasi et al, 2007;Broad et al, 2008;Gunthorpe and Chizh, 2009;Pal et al, 2009).…”