Adamantyl Analogues of Paracetamol as Potent Analgesic Drugs via Inhibition of TRPA1

Fresno, Nieves; Pérez-Fernández, Ruth; Goicoechea, Carlos; Alkorta, Ibón; Fernández-Carvajal, Asia; Martínez, Rafael Giménez; Quirce, Susana; Ferrer-Montiel, Antonio; Martı́n, Marı́a Isabel; Goya, Pilar; Elguero, José

doi:10.1371/journal.pone.0113841

Cited by 17 publications

(10 citation statements)

References 47 publications

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“…mTRPA1 is inhibited by tannic acid (612) and by the extract of the medicinal plant Pterodon pubescens Benth, containing a mixture of nine sesquiterpenes and seven diterpenes (605). (850), and the paracetamol (acetaminophen) analog 6a/b (256). The antipyretic effect of paracetamol, however, is not related to its action of TRPA1 that lead to hypothermia, but to prostaglandin inhibition in the brain (529).…”

Section: Trpa1 Antagonismmentioning

confidence: 99%

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Talavera

Startek

Alvarez‐Collazo

et al. 2020

Physiological Reviews

257

274

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The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.

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Section: Trpa1 Antagonismmentioning

confidence: 99%

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Talavera

Startek

Alvarez‐Collazo

et al. 2020

Physiological Reviews

257

274

View full text Add to dashboard Cite

show abstract

“…Paracetamol (acetaminophen) has TRPA1-independent antipyretic effects [ 182 ] and TRPA1-dependent effects on pain [ 183 ]. The electrophilic metabolites N-acetyl-p-benzoquinone imine (NAPQI, hepatotoxic metabolite) and p-benzoquinone, but not paracetamol itself, activate TRPA1 [ 82 ].…”

Section: Activation and Desensitization Of Trpa1 And Trpv1mentioning

confidence: 99%

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

Bousquet

Czarlewski²,

Zuberbier

et al. 2021

Int Arch Allergy Immunol

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In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.

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“…Some derivatives of 1-aminoadamantane are investigated as potential analgesic compounds because of their agonist activity at CB 2 or/and CB 1 cannabinoid receptors [36] [37]. Replacement of the phenyl ring in molecule of paracetamol (acetaminophen) with an adamantyl moiety produced a new 1-aminoadamantane derivative with analgesic properties that can only be explained by selective TRPA 1 channel antagonist activity rather than by COX inhibition or by direct interaction with cannabinoid receptors [38]. Molecules containing 2-aminoadamantane-1-carboxylic acid and 2-aminoadamantane fragments have antinociceptive properties owing to the inhibition of P 2 X 7 -triggered glutamate release [39].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

Ivanova¹,

Kapitsa²,

Sukhorukova³

et al. 2016

APD

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The efficacy of some aminoadamantane derivatives used as neurodegeneration treatments is due to their ability to block NMDA receptors. But this mechanism of pharmacological action can also produce analgesic activity. Analgesic properties of two aminoadamantanes, amantadine (20 mg/kg) and hemantane (20 mg/kg), which were uncompetitive NMDA receptor antagonists, were assessed in rodent models of pain induced by different pain stimuli (tail-flick test, acetic twitches test in mice and formalin test in rats). Additionally, the anti-inflammatory properties of hemantane and amantadine were evaluated in mice with acetic peritonitis and in rats with hind paw edema induced by formalin injection. The results of our study demonstrate that the analgesic activity of the 1-aminoadamantane amantadine differs from the 2-aminoadamantane hemantane. The analgesic activity of amantadine administered intraperitoneally was more pronounced in the case of acute thermal pain in mice compared to hemantane, and only amantadine had a significant analgesic effect on the acute early phase of formalin pain in rats induced by the effect of the algogen on the primary sensory afferents. Hemantane was more effective than amantadine for relieving pain produced by inflammation owing to its pronounced anti-inflammatory activity: only hemantane decreased the amount of acetic twitches in mice that received drugs orally and was effective in the tonic phase of formalin pain in rats.

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Adamantyl Analogues of Paracetamol as Potent Analgesic Drugs via Inhibition of TRPA1

Cited by 17 publications

References 47 publications

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

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