{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:25:25Z","timestamp":1789608325805,"version":"build-2803163510"},"reference-count":103,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T00:00:00Z","timestamp":1687132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Research Council","award":["16\/646"],"award-info":[{"award-number":["16\/646"]}]},{"name":"Health Research Council","award":["22\/331"],"award-info":[{"award-number":["22\/331"]}]},{"name":"Health Research Council","award":["R01DA01851"],"award-info":[{"award-number":["R01DA01851"]}]},{"name":"NIH","award":["16\/646"],"award-info":[{"award-number":["16\/646"]}]},{"name":"NIH","award":["22\/331"],"award-info":[{"award-number":["22\/331"]}]},{"name":"NIH","award":["R01DA01851"],"award-info":[{"award-number":["R01DA01851"]}]},{"name":"Kentucky Medical Services Foundation Chair","award":["16\/646"],"award-info":[{"award-number":["16\/646"]}]},{"name":"Kentucky Medical Services Foundation Chair","award":["22\/331"],"award-info":[{"award-number":["22\/331"]}]},{"name":"Kentucky Medical Services Foundation Chair","award":["R01DA01851"],"award-info":[{"award-number":["R01DA01851"]}]},{"name":"Victoria University of Wellington, New Zealand","award":["16\/646"],"award-info":[{"award-number":["16\/646"]}]},{"name":"Victoria University of Wellington, New Zealand","award":["22\/331"],"award-info":[{"award-number":["22\/331"]}]},{"name":"Victoria University of Wellington, New Zealand","award":["R01DA01851"],"award-info":[{"award-number":["R01DA01851"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light\u2013dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects.<\/jats:p>","DOI":"10.3390\/molecules28124848","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T01:59:30Z","timestamp":1687226370000},"page":"4848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-444X","authenticated-orcid":false,"given":"Ross","family":"van de Wetering","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Ewald","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Welsh","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Kornberger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0108-8764","authenticated-orcid":false,"given":"Samuel E.","family":"Williamson","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan D.","family":"McElroy","sequence":"additional","affiliation":[{"name":"Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo R.","family":"Butelman","sequence":"additional","affiliation":[{"name":"Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-8052","authenticated-orcid":false,"given":"Thomas E.","family":"Prisinzano","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-553X","authenticated-orcid":false,"given":"Bronwyn M.","family":"Kivell","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1056\/NEJMra1511480","article-title":"Neurobiologic Advances from the Brain Disease Model of Addiction","volume":"374","author":"Volkow","year":"2016","journal-title":"N. 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