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In order to discover novel non\u2010morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in\u2010house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel \u03bc\u2010OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R\u2010group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new G\n                    <jats:sub>i<\/jats:sub>\n                    \u2010protein\u2010biased compound, 1\u2010{5\u2010(3\u2010chlorophenyl)\u20107,8\u2010dimethoxy\u20103\u2010[4\u2010(methylsulfonyl)benzyl]\u20103\n                    <jats:italic>H<\/jats:italic>\n                    \u2010pyrazolo[3,4\u2010\n                    <jats:italic>c<\/jats:italic>\n                    ]isoquinolin\u20101\u2010yl}\u2010\n                    <jats:italic>N<\/jats:italic>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010dimethylmethanamine, showed an EC\n                    <jats:sub>50<\/jats:sub>\n                    value of 179\u2005n\n                    <jats:sc>m<\/jats:sc>\n                    against the \u03bc\u2010OR. This resulted in significant pain relief for mice in the phase\u2005II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G\u2010protein\u2010coupled receptors.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.201900418","type":"journal-article","created":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T03:05:02Z","timestamp":1564455902000},"page":"1783-1794","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Discovery of Novel Biased Opioid Receptor Ligands through Structure\u2010Based Pharmacophore Virtual Screening and Experiment"],"prefix":"10.1002","volume":"14","author":[{"given":"Pyeonghwa","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Biomedical Science and Engineering Gwangju Institute of Science and Technology  123 Cheomdan-gwagiro Buk-gu 61005 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo\u2010Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Materials and Process Simulation Center (MC-139-74) California Institute of Technology  Pasadena California 91125 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanjie","family":"Li","sequence":"additional","affiliation":[{"name":"Materials and Process Simulation Center (MC-139-74) California Institute of Technology  Pasadena California 91125 USA"},{"name":"College of Chemistry Beijing Normal University  Beijing 100875 P. 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