{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:07:21Z","timestamp":1787162841787,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/GMS","award":["R01GM123746"],"award-info":[{"award-number":["R01GM123746"]}]},{"name":"NIH\/GMS","award":["R35GM141802"],"award-info":[{"award-number":["R35GM141802"]}]},{"name":"NIH\/GMS","award":["1I01BX004763"],"award-info":[{"award-number":["1I01BX004763"]}]},{"name":"NIH\/GMS","award":["MH122379"],"award-info":[{"award-number":["MH122379"]}]},{"name":"NIH\/GMS","award":["T32GM135169"],"award-info":[{"award-number":["T32GM135169"]}]},{"name":"CU Medicine Endowment","award":["R01GM123746"],"award-info":[{"award-number":["R01GM123746"]}]},{"name":"CU Medicine Endowment","award":["R35GM141802"],"award-info":[{"award-number":["R35GM141802"]}]},{"name":"CU Medicine Endowment","award":["1I01BX004763"],"award-info":[{"award-number":["1I01BX004763"]}]},{"name":"CU Medicine Endowment","award":["MH122379"],"award-info":[{"award-number":["MH122379"]}]},{"name":"CU Medicine Endowment","award":["T32GM135169"],"award-info":[{"award-number":["T32GM135169"]}]},{"name":"Department of Anesthesiology start-up funds","award":["R01GM123746"],"award-info":[{"award-number":["R01GM123746"]}]},{"name":"Department of Anesthesiology start-up funds","award":["R35GM141802"],"award-info":[{"award-number":["R35GM141802"]}]},{"name":"Department of Anesthesiology start-up funds","award":["1I01BX004763"],"award-info":[{"award-number":["1I01BX004763"]}]},{"name":"Department of Anesthesiology start-up funds","award":["MH122379"],"award-info":[{"award-number":["MH122379"]}]},{"name":"Department of Anesthesiology start-up funds","award":["T32GM135169"],"award-info":[{"award-number":["T32GM135169"]}]},{"name":"VA Merit","award":["R01GM123746"],"award-info":[{"award-number":["R01GM123746"]}]},{"name":"VA Merit","award":["R35GM141802"],"award-info":[{"award-number":["R35GM141802"]}]},{"name":"VA Merit","award":["1I01BX004763"],"award-info":[{"award-number":["1I01BX004763"]}]},{"name":"VA Merit","award":["MH122379"],"award-info":[{"award-number":["MH122379"]}]},{"name":"VA Merit","award":["T32GM135169"],"award-info":[{"award-number":["T32GM135169"]}]},{"name":"NIH T32 Fellow","award":["R01GM123746"],"award-info":[{"award-number":["R01GM123746"]}]},{"name":"NIH T32 Fellow","award":["R35GM141802"],"award-info":[{"award-number":["R35GM141802"]}]},{"name":"NIH T32 Fellow","award":["1I01BX004763"],"award-info":[{"award-number":["1I01BX004763"]}]},{"name":"NIH T32 Fellow","award":["MH122379"],"award-info":[{"award-number":["MH122379"]}]},{"name":"NIH T32 Fellow","award":["T32GM135169"],"award-info":[{"award-number":["T32GM135169"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Although opioids are effective in treating pain, they cause serious side effects. The use of regional anesthesia, although effective in the perioperative period, may not be suitable if mobility and lack of numbness is desired. Hence, there is a clear need for novel pain therapies. Low-voltage activated (T-type) calcium channels (CaV3.2 isoform) could be a promising therapeutic target for the development of novel pain therapies. Indeed, our published findings suggest that novel neuroactive steroid (NAS) analogs that modulate the activity of CaV3.2 channels have unique anti-nociceptive properties. However, the concern with current NASs appears to be their hypnotic\/sedative properties, thus potentially hindering the future development of NASs for novel pain therapies. Hence, we developed a new line of NASs that are effective blockers of neuronal CaV3.2 channels in pain pathways while having more favorable pharmacodynamic properties, i.e., lack of sedative\/hypnotic side effects. We present two promising novel analogs of NASs\u2014B372 ((3\u03b2,5\u03b1,17\u03b2)-3-Hydroxyandrostan-17-carbonitrile) and YX23 ((3\u03b2,5\u03b1,17\u03b2)-3-Methoxyestran-17-ol). Using an in vitro approach, we show that B372 and YX23 are effective in blocking CaV3.2 channels. Using an in vivo approach, we show that they are effective anti-nociceptives in wild-type but not CaV3.2 knock-out mice. Importantly, we show that they lack sedative\/hypnotic effects.<\/jats:p>","DOI":"10.3390\/biom15081175","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T07:53:12Z","timestamp":1755503592000},"page":"1175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Neuroactive Steroid Analogs and Voltage-Dependent Blockers of CaV3.2 Currents, B372 and YX23, Are Effective Anti-Nociceptives with Diminished Sedative Properties in Intact Female Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4266-9776","authenticated-orcid":false,"given":"Benjamin","family":"Volvovitz","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-123X","authenticated-orcid":false,"given":"Rakib","family":"Miah","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1432-8301","authenticated-orcid":false,"given":"Kibeom","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Keimyung University Dongsan Hospital, School of Medicine, Keimyung University, 1035, Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, 120-1, Neungdong-ro (Hwayang-dong), Gwangjin-gu, Seoul 05030, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1862-1510","authenticated-orcid":false,"given":"Raul","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1108-3286","authenticated-orcid":false,"given":"Yuanjiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2106-2855","authenticated-orcid":false,"given":"Mingxing","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA"},{"name":"Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-0391","authenticated-orcid":false,"given":"Slobodan M.","family":"Todorovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Jevtovic-Todorovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"ref_1","unstructured":"Santo, L., and Kang, K. 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