Synthesis of New Heterocyclic μ-Opioid Receptor Agonists

Abstract

Human μ-opioid receptor agonists such as morphine are the most efficacious drugs for several pains. However, there are many side effects including nausea, vomiting, constipation, respiratory suppression and tolerance. Recent studies have shown that these side effects are related to ß-arrestin recruitment pathway. Previously, a virtual screening was performed through a docking study using the GIST database containing various scaffolds for β-turn mimetic and various heterocyclic compounds with the active homology model of human μ-opioid receptor developed by Caltech. Resultingly, LDD3101 is selected as a hit compound. Then, after optimization through R-group screening, activity evaluation was performed on the newly synthesized compounds using two different in vitro systems. Of the total 10 synthesized compounds, compound 12 found a new lead compound showing an EC50 of 0.94 μM at MOR. Furthermore, all synthesized compounds showed minimal β-arrestin recruitment. Therefore, this study suggested the possibility of discovering new heterocyclic μ-opioid receptor agonists.