{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T20:35:07Z","timestamp":1768682107169,"version":"3.49.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["201704 201909"],"award-info":[{"award-number":["201704 201909"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY024727 DA003934 Y1-DA1101"],"award-info":[{"award-number":["EY024727 DA003934 Y1-DA1101"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008920","name":"University of Saskatchewan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008920","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the <jats:italic>R<\/jats:italic>-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the <jats:italic>S<\/jats:italic>-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the <jats:italic>R<\/jats:italic> and <jats:italic>S<\/jats:italic>-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. The <jats:italic>R<\/jats:italic>-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects <jats:italic>in vitro<\/jats:italic>, and PAM effects in the <jats:italic>in vivo<\/jats:italic> behavioral triad, indicating that the <jats:italic>in vivo<\/jats:italic> activity of these ligands may occur <jats:italic>via<\/jats:italic> PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington\u2019s disease.<\/jats:p>","DOI":"10.3389\/fphar.2022.919605","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T06:27:42Z","timestamp":1666679262000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593"],"prefix":"10.3389","volume":"13","author":[{"given":"Asher L.","family":"Brandt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumanta","family":"Garai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayat","family":"Zagzoog","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dow P.","family":"Hurst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley A.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger G.","family":"Pertwee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory H.","family":"Imler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia H.","family":"Reggio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganesh A.","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert B.","family":"Laprairie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1080\/03602532.2018.1428341","article-title":"The future of type 1 cannabinoid receptor allosteric ligands","volume":"50","author":"Alaverdashvili","year":"2018","journal-title":"Drug Metab. 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