Discovery of pyrazole-1-carboxamide derivatives as novel Gi-biased μ-opioid receptor agonists

mu-Opioid receptor (MOR) Gi-biased agonists with no recruitment of beta-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship (SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate (cAMP) levels for the Gi pathway and beta-arrestin recruitment in MOR/kappa-opioid receptor/delta opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration value of 87.1 nM and no activity in the MOR beta-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.

Automated summary

In this study, a selective Gi-biased mu-opioid receptor agonist was developed through design, synthesis and structure-activity relationship analysis. The agonist exhibited dose-dependent pain relief efficacy in in vivo experiments.