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Enantiomer pairs of eight <jats:italic>tert<\/jats:italic>\u2010leucinate or valinate indole\u2010 and indazole\u20103\u2010carboxamide SCRAs were synthesized and their CB<jats:sub>1<\/jats:sub> potency and efficacy assessed using an <jats:italic>in vitro<\/jats:italic> \u03b2\u2010arrestin recruitment assay in a HEK239T stable cell system. A chiral high\u2010performance liquid chromatography method with photodiode array and\/or quadrupole time\u2010of\u2010flight\u2010mass spectrometry detection (HPLC\u2010PDA and HPLC\u2010PDA\u2010QToF\u2010MS) was applied to 177 SCRA\u2010infused paper samples seized in Scottish prisons between 2018 and 2020. In most samples, SCRAs were almost enantiopure (<jats:italic>S<\/jats:italic>)\u2010enantiomer (&gt;98% of total chromatographic peak area), although in some (<jats:italic>n<\/jats:italic> = 18), 2% to 16% of the (<jats:italic>R<\/jats:italic>)\u2010enantiomer was detected. (<jats:italic>S<\/jats:italic>)\u2010enantiomers are consistently more potent than (<jats:italic>R<\/jats:italic>)\u2010enantiomers and often more efficacious. The importance of SCRA\u2010CB<jats:sub>1<\/jats:sub> receptor interactions in the \u201chead\u201d or \u201clinked group\u201d moiety is demonstrated, with the conformation of the \u201cbulky\u201d <jats:italic>tert<\/jats:italic>\u2010leucinate group greatly affecting potency (by up to a factor of 374), significantly greater than the difference observed between valinate SCRA enantiomers. (<jats:italic>S<\/jats:italic>)\u2010MDMB\u20104en\u2010PINACA, (<jats:italic>S<\/jats:italic>)\u20104F\u2010MDMB\u2010BINACA, and (<jats:italic>S<\/jats:italic>)\u20105F\u2010MDMB\u2010PICA are currently the most prevalent SCRAs in Scottish prisons, and all have similar high potency (EC<jats:sub>50<\/jats:sub>, 1\u20135 nM) and efficacy. Infused paper samples were compared using estimated intrinsic efficacy at the CB<jats:sub>1<\/jats:sub> receptor (EIE<jats:sub>CB1<\/jats:sub>) to evaluate samples with variable SCRA content. Given their similar potency and efficacy, any variation in CB<jats:sub>1<\/jats:sub> receptor\u2010mediated psychoactive effects are likely to derive from variation in dose, mode of use, pharmacokinetic differences, and individual factors affecting the user, rather than differences in the specific SCRA present.<\/jats:p>","DOI":"10.1002\/dta.2965","type":"journal-article","created":{"date-parts":[[2020,11,8]],"date-time":"2020-11-08T05:14:40Z","timestamp":1604812480000},"page":"628-643","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Shape matters: The application of activity\u2010based <i>in vitro<\/i> bioassays and chiral profiling to the pharmacological evaluation of synthetic cannabinoid receptor agonists in drug\u2010infused papers seized in prisons"],"prefix":"10.1002","volume":"13","author":[{"given":"Lysbeth H.","family":"Antonides","sequence":"first","affiliation":[{"name":"Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8654-1371","authenticated-orcid":false,"given":"Annelies","family":"Cannaert","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2322-0367","authenticated-orcid":false,"given":"Caitlyn","family":"Norman","sequence":"additional","affiliation":[{"name":"Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-0887","authenticated-orcid":false,"given":"Niamh","family":"NicD\u00e1eid","sequence":"additional","affiliation":[{"name":"Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-7754","authenticated-orcid":false,"given":"Oliver B.","family":"Sutcliffe","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences Manchester Metropolitan University  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-4759","authenticated-orcid":false,"given":"Christophe P.","family":"Stove","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-5779","authenticated-orcid":false,"given":"Craig","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,9]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/346561a0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/365061a0"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(97)82001-3"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003004"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-psych-113011-143739"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101301"},{"key":"e_1_2_6_8_1","volume-title":"European Drug Report 2019, Trends and Developments","author":"European Monitoring Centre for Drugs and Drug Addiction","year":"2019"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2019.1661425"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp1505328"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02693-7"},{"key":"e_1_2_6_12_1","article-title":"Post\u2010mortem toxicology: a systematic review of death cases involving synthetic cannabinoid receptor agonists","volume":"11","author":"Giorgetti A","year":"2020","journal-title":"Front Psych"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.2767"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugpo.2016.10.003"},{"key":"e_1_2_6_15_1","unstructured":"PrisonHM&Probation Service.Her Majesty's prison and probation service annual report and accounts 2018\u201019.2019Available from:https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/818788\/HMPPS_Annual_Report_and_Accounts_2018\u201019__web_.pdf. 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