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Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

ABSTRACT: Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.

SUBMITTER: Fresno N

PROVIDER: S-EPMC4249970 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

Fresno Nieves N Pérez-Fernández Ruth R Goicoechea Carlos C Alkorta Ibon I Fernández-Carvajal Asia A de la Torre-Martínez Roberto R Quirce Susana S Ferrer-Montiel Antonio A Martín M Isabel MI Goya Pilar P Elguero José J

PloS one 20141201 12

Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties ...[more]

PMID: 25438056

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Project description:BackgroundChronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown.MethodsBased on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro.ResultsIntrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol.ConclusionsIn the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

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Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

Publications

Adamantyl analogues of paracetamol as potent analgesic drugs via inhibition of TRPA1.

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