Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization

Qiao, Zhen; Luo, Jiajie; Tang, Yong-Bo; Zhou, Qiqi; Qi, Hang; Yin, Zhengji; Tang, Xiaowen; Zhu, Wei; Zhang, Yanru; Wang, Ningning; Wang, Kewei

doi:10.1021/acs.jmedchem.1c01579

Cited by 14 publications

(13 citation statements)

References 45 publications

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“…Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), two nonselective cation channels, are mostly expressed in nociceptive neurons and play critical roles in pain generation, [ 37‐38 ] and are promising targets for pain therapy. [ 39 ] TRPV1 can be activated by noxious chemical stimuli such as capsaicin, and TRPA1 can be activated by irritants including allyl‐isothiocyanate (AITC), cinnamaldehyde, allicin, aldehydes, nitrogen, and reactive‐ oxygen species.…”

Section: Resultsmentioning

confidence: 99%

Highly Oxygenated Dimeric Grayanane Diterpenoids as Analgesics: TRPV1 and TRPA1 Dual Antagonists from Rhododendron molle

et al. 2022

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Six highly oxygenated dimeric grayanane diterpenoids (1-6) including three new ones, bismollethers A-C (1-3), were isolated from the flowers of Rhododendron molle collected at Qichun, Hubei, China. The structures and relative configurations of 1-6 were determined by comprehensive spectroscopic data analysis and 13 C NMR calculation with DP4+ analysis. The absolute configurations of bismollethers A-C (1-3) and birhodomollein B (5) were indubitably assigned by single-crystal X-ray diffraction analysis, revealing the head-to-tail linking manner of diterpenoid monomers. Bismollether A (1) is a caged dimeric grayanane diterpenoid linked through two oxygen-bridges of C-2−O−C-14ʹ and C-14−O−C-2ʹ, featuring a unique 1,8-dioxacyclotetradecane motif. The plausible biosynthesis pathways of 1-6 are proposed. All the isolates displayed significant analgesic activities and their structure-activity relationships were discussed. Grayanane diterpenoid dimers were found to be TRPV1 and TRPA1 dual antagonists, and docking studies provide a structural basis to design potent analgesics.

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Section: Resultsmentioning

confidence: 99%

Highly Oxygenated Dimeric Grayanane Diterpenoids as Analgesics: TRPV1 and TRPA1 Dual Antagonists from Rhododendron molle

et al. 2022

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“…Although strongly facilitating the determination of cell and circuit function while reducing variability 3 , these approaches are neither widely nor routinely used due to various burdensome requirements for their use. The ideal tool would specifically modulate the nociceptor’s activity by controlling endogenous pain-related ion channels 10 , 11 without the need for (i) genetic manipulation, (ii) viral infection, (iii) surgery, and (iv) extensive animal housing. In addition, this compound (i) would be in its inactivated state in the dark, enabling long-term experiments, (ii) would be ethically relevant by being non-invasive, (iii) would allow rapid, reproducible, and reversible control of pain in a physiological and pathological manner, and (iv) would be amenable to be used in different species.…”

Section: Introductionmentioning

confidence: 99%

A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

et al. 2023

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By endowing light control of neuronal activity, optogenetics and photopharmacology are powerful methods notably used to probe the transmission of pain signals. However, costs, animal handling and ethical issues have reduced their dissemination and routine use. Here we report LAKI (Light Activated K+ channel Inhibitor), a specific photoswitchable inhibitor of the pain-related two-pore-domain potassium TREK and TRESK channels. In the dark or ambient light, LAKI is inactive. However, alternating transdermal illumination at 365 nm and 480 nm reversibly blocks and unblocks TREK/TRESK current in nociceptors, enabling rapid control of pain and nociception in intact and freely moving mice and nematode. These results demonstrate, in vivo, the subcellular localization of TREK/TRESK at the nociceptor free nerve endings in which their acute inhibition is sufficient to induce pain, showing LAKI potential as a valuable tool for TREK/TRESK channel studies. More importantly, LAKI gives the ability to reversibly remote-control pain in a non-invasive and physiological manner in naive animals, which has utility in basic and translational pain research but also in in vivo analgesic drug screening and validation, without the need of genetic manipulations or viral infection.

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“…As shown in Figure 4 A, 1 μM CPIPC had no detectable activation of TRPV2 channel that was activated by agonist 2-APB [ 25 ]. Similarly, CPIPC at 1 μM caused no activation of TRPV3, TRPV4 or TRPA1 currents ( Figure 4 B–D), as compared with the channel activation by their agonists 2-APB for TRPV3, GSK1016790A for TRPV4 or AITC for TRPA1 [ 25 , 26 , 27 ]. We also evaluated the effect of CPIPC or capsaicin on Nav1.7 channels expressed in HEK293 cells.…”

Section: Resultsmentioning

confidence: 91%

Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain

Dong

Zhou²,

Liang

et al. 2022

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Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, predominantly expressed in a subset of peripheral sensory neurons for pain signaling. Topical application of agonist capsaicin for desensitizing TRPV1 currents has been approved for relief of chronic pain. However, the potent TRPV1 capsaicin is not ingestible and even topical capsaicin causes common side effects such as skin irritation, swelling, erythema and pruritus, suggesting that a mild TRPV1 agonist might be helpful for reducing side effects while reliving pain. In this study, we reported on a partial and selective TRPV1 agonist 4-(5-chloropyridin-2-yl)-N-(1H-indazol-6-yl)piperazine-1-carboxamide named CPIPC that was modified based on targeting the residue Arg557, important for conversion between the channel antagonism and agonism. Whole-cell patch clamp recordings indicated a concentration-dependent activation of TRPV1 currents by CPIPC with an EC50 of 1.56 ± 0.13 μM. The maximum efficacy of CPIPC (30 μM) was about 60% of saturated capsaicin (10 μM). Repetitive additions of CPIPC caused TRPV1 current desensitization in both TRPV1-expressing HEK293 cells and dorsal root ganglion (DRG) sensory neurons. Oral administration of CPIPC dose-dependently alleviated inflammatory pain in mice. Further site-directed mutagenesis combined with molecular docking revealed that residue Arg557 is critical for TRPV1 activation by CPIPC. Taken together, we identified a novel partial and selective TRPV1 agonist CPIPC that exhibits antinociceptive activity in mice.

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Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization

Cited by 14 publications

References 45 publications

Highly Oxygenated Dimeric Grayanane Diterpenoids as Analgesics: TRPV1 and TRPA1 Dual Antagonists from Rhododendron molle

Highly Oxygenated Dimeric Grayanane Diterpenoids as Analgesics: TRPV1 and TRPA1 Dual Antagonists from Rhododendron molle

A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain

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