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However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse, and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2. Here, we report the identification of C2230, an aryloxy-hydroxypropylamine, as a Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 blocker. C2230 trapped and stabilized inactivated Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled-receptor\u2013independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via 3 different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 blockers, making it a promising lead compound for analgesic development.\n                  <\/jats:p>","DOI":"10.1172\/jci177429","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T12:01:04Z","timestamp":1733832064000},"source":"Crossref","is-referenced-by-count":24,"title":["C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models"],"prefix":"10.1172","volume":"135","author":[{"given":"Cheng","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, and"},{"name":"Pain Research Center, New York University, New York, New York, USA."},{"name":"The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather N.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Hestehave","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, and"},{"name":"Pain Research Center, New York University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick J.","family":"Rodr\u00edguez-Palma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Loya-Lopez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Calderon-Rivera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paz","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, and"},{"name":"Pain Research Center, New York University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-4820","authenticated-orcid":true,"given":"Tyler S.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siva Rama Raju","family":"Kanumuri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijal","family":"Shah","sequence":"additional","affiliation":[{"name":"Center for Orofacial Pain and Temporomandibular Disorders, Department of Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihar R.","family":"Panigrahi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, New York University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Perez-Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan K.","family":"Schackmuth","sequence":"additional","affiliation":[{"name":"University of Texas at Dallas, School of Behavioral and Brain Sciences, Department of Neuroscience, Center for Advanced Pain Studies, Richardson, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani","family":"Ruparel","sequence":"additional","affiliation":[{"name":"Department of Endodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, and Center for Pain Therapeutics and Addiction Research, San Antonio, Texas, 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