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Accordingly, new and selective low\u2010efficacy MOR agonists are of interest. A novel set of chiral C9\u2010substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high\u2010to\u2010low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand\u2010stimulated [<jats:sup>35<\/jats:sup>S]GTP\u0263S binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high\u2010efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower\u2010efficacy MOR agonists. In the ligand\u2010stimulated [<jats:sup>35<\/jats:sup>S]GTP\u0263S binding assay, seven phenylmorphans had graded levels of sub\u2010buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and \u22651\u2009h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high\u2010efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR\u2010selective ligands with graded MOR efficacy and utility for further behavioral studies in mice.<\/jats:p>","DOI":"10.1002\/prp2.1111","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T04:20:01Z","timestamp":1688012401000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Role of efficacy as a determinant of locomotor activation by mu\u2010opioid receptor (<scp>MOR<\/scp>) ligands in female and male mice. <scp>II<\/scp>. Effects of novel <scp>MOR<\/scp>\u2010selective phenylmorphans with high\u2010to\u2010low <scp>MOR<\/scp> efficacy"],"prefix":"10.1002","volume":"11","author":[{"given":"Edna J.","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nima","family":"Nassehi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric W.","family":"Bow","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana R.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene\u00a0S.","family":"Gutman","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur E.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Lutz","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel A.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenner C.","family":"Rice","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Sulima","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section Molecular Targets and Medications Discovery Branch, NIDA and NIAAA  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana E.","family":"Selley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-645X","authenticated-orcid":false,"given":"S. Stevens","family":"Negus","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"e_1_2_13_2_1","first-page":"355","volume-title":"Goodman and Gilman's: the Pharmacological Basis of Therapeutics, 13e","author":"Yaksh T","year":"2018"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.119.119214"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-052120-091058"},{"key":"e_1_2_13_5_1","first-page":"496","article-title":"Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor\u2010stimulated [35S]GTP gamma S binding in mMOR\u2010CHO cells and rat thalamus","volume":"285","author":"Selley DE","year":"1998","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/ael051"},{"key":"e_1_2_13_7_1","first-page":"330","article-title":"Pharmacological characterization of the cloned kappa\u2010, delta\u2010, and mu\u2010opioid receptors","volume":"45","author":"Raynor K","year":"1994","journal-title":"Mol Pharmacol"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2009.02.078"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.10.134"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(81)90067-8"},{"key":"e_1_2_13_11_1","first-page":"1044","article-title":"Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice","volume":"262","author":"Pick CG","year":"1992","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_13_12_1","first-page":"184","article-title":"Drug discrimination in human postaddicts: agonist\u2010antagonist opioids","volume":"250","author":"Preston KL","year":"1989","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_13_13_1","first-page":"827","article-title":"Opioid efficacy in a C6 glioma cell line stably expressing the human kappa opioid receptor","volume":"288","author":"Remmers AE","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0376-8716(85)90066-3"},{"key":"e_1_2_13_15_1","first-page":"259","article-title":"Kappa\u2010opioid receptor effects of butorphanol in rhesus monkeys","volume":"290","author":"Vivian JA","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196455"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0MD00104J"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm061325e"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28124795"},{"key":"e_1_2_13_20_1","unstructured":"RiceKC JacobsonAE LiF et al.Biased potent opioid\u2010like agonists as improved medications to treat chronic and acute pain and methods of using the same.2019. 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