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In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at \u03ba-(K)OR appeared in 5\u2032-esters (ethyl 24 and propyl 30), which retained TSPO interaction (\u03bcM). 7-Deaza modification of C2-(arylethynyl)-5\u2032-esters but not 4\u2032-truncation enhanced KOR affinity (MRS7299 28 and 29, Ki \u2248 40 nM), revealed \u03bc-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis for KOR recognition.<\/jats:p>","DOI":"10.1021\/acsomega.8b01237","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T14:04:06Z","timestamp":1538661846000},"page":"12658-12678","source":"Crossref","is-referenced-by-count":16,"title":["Repurposing of a Nucleoside Scaffold from Adenosine\nReceptor Agonists to Opioid Receptor Antagonists"],"prefix":"10.1021","volume":"3","author":[{"given":"Dilip K.","family":"Tosh","sequence":"first","affiliation":[{"name":"National Institutes of Health , , 9000 Rockville Pike , , ,","place":["Bethesda, Maryland, United States, 20892"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-2050","authenticated-orcid":true,"given":"Antonella","family":"Ciancetta","sequence":"additional","affiliation":[{"name":"National Institutes of Health , , 9000 Rockville Pike , , ,","place":["Bethesda, Maryland, United States, 20892"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Mannes","sequence":"additional","affiliation":[{"name":"National Institutes of Health , , 9000 Rockville Pike , , ,","place":["Bethesda, Maryland, United States, 20892"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Warnick","sequence":"additional","affiliation":[{"name":"National Institutes of Health , , 9000 Rockville Pike , , ,","place":["Bethesda, Maryland, United States, 20892"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Janowsky","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University , , 3710 S.W. 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