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For the development of novel Gi\u2010biased MOR agonists, the design, synthesis, and structure\u2013activity relationship\u00a0(SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (<jats:bold>2a<\/jats:bold>) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate\u00a0(cAMP) levels for the Gi pathway and \u03b2\u2010arrestin recruitment in MOR\/\u03ba\u2010opioid receptor\/\u03b4 opioid receptor. An optimized selective Gi\u2010biased agonist, Compound <jats:bold>17a<\/jats:bold>, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration value\u00a0of 87.1\u2009nM and no activity in the MOR \u03b2\u2010arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound <jats:bold>17a<\/jats:bold> was confirmed in a dose\u2010dependent manner with spinal nerve ligation and cisplatin\u2010induced peripheral neuropathy rodent neuropathic pain models.<\/jats:p>","DOI":"10.1002\/ddr.21980","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T05:34:29Z","timestamp":1663652069000},"page":"1600-1612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Discovery of pyrazole\u20101\u2010carboxamide derivatives as novel Gi\u2010biased \u03bc\u2010opioid receptor agonists"],"prefix":"10.1002","volume":"83","author":[{"given":"Jae\u2010Hoon","family":"Jung","sequence":"first","affiliation":[{"name":"School of Life Sciences Gwangju Institute of Science and Technology (GIST) Gwangju Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In 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