{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:44:54Z","timestamp":1790671494547,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81973299"],"award-info":[{"award-number":["81973299"]}]},{"name":"National Natural Science Foundation of China","award":["81573410"],"award-info":[{"award-number":["81573410"]}]},{"name":"National Natural Science Foundation of China","award":["82104149"],"award-info":[{"award-number":["82104149"]}]},{"name":"National Natural Science Foundation of China","award":["2018ZX09711001-004-006"],"award-info":[{"award-number":["2018ZX09711001-004-006"]}]},{"name":"National Natural Science Foundation of China","award":["ZR2021QH192"],"award-info":[{"award-number":["ZR2021QH192"]}]},{"name":"National Natural Science Foundation of China","award":["ZR2020QH100"],"award-info":[{"award-number":["ZR2020QH100"]}]},{"name":"Ministry of Science and Technology of China","award":["81973299"],"award-info":[{"award-number":["81973299"]}]},{"name":"Ministry of Science and Technology of China","award":["81573410"],"award-info":[{"award-number":["81573410"]}]},{"name":"Ministry of Science and Technology of China","award":["82104149"],"award-info":[{"award-number":["82104149"]}]},{"name":"Ministry of Science and Technology of China","award":["2018ZX09711001-004-006"],"award-info":[{"award-number":["2018ZX09711001-004-006"]}]},{"name":"Ministry of Science and Technology of China","award":["ZR2021QH192"],"award-info":[{"award-number":["ZR2021QH192"]}]},{"name":"Ministry of Science and Technology of China","award":["ZR2020QH100"],"award-info":[{"award-number":["ZR2020QH100"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["81973299"],"award-info":[{"award-number":["81973299"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["81573410"],"award-info":[{"award-number":["81573410"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["82104149"],"award-info":[{"award-number":["82104149"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["2018ZX09711001-004-006"],"award-info":[{"award-number":["2018ZX09711001-004-006"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["ZR2021QH192"],"award-info":[{"award-number":["ZR2021QH192"]}]},{"name":"Shandong Provincial Natural Science Foundation of China","award":["ZR2020QH100"],"award-info":[{"award-number":["ZR2020QH100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u00b1 0.13 \u03bcM. The maximum efficacy of CPIPC (30 \u03bcM) was about 60% of saturated capsaicin (10 \u03bcM). 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.<\/jats:p>","DOI":"10.3390\/molecules27175428","type":"journal-article","created":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T02:04:32Z","timestamp":1661479472000},"page":"5428","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Identification of a Partial and Selective TRPV1 Agonist CPIPC for Alleviation of Inflammatory Pain"],"prefix":"10.3390","volume":"27","author":[{"given":"Liying","family":"Dong","sequence":"first","affiliation":[{"name":"Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Qilu Medical University, Zibo 255300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5675-4712","authenticated-orcid":false,"given":"Yani","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"},{"name":"Institute of Innovative Drug Discovery, Qingdao University Medical College, 38 Dengzhou Road, Qingdao 266021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewei","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao 266073, China"},{"name":"Institute of Innovative Drug Discovery, Qingdao University Medical College, 38 Dengzhou Road, Qingdao 266021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1146\/annurev.neuro.24.1.487","article-title":"The vanilloid receptor: A molecular gateway to the pain pathway","volume":"24","author":"Caterina","year":"2001","journal-title":"Annu. 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