Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted µ/δ/κ opioid receptor (2019-2022).

The opioids have been used for more than a thousand years and are not only the most widely prescribed drugs for moderate to severe pain and acute pain, but also the preferred drugs. However, their non-analgesic effects, especially respiratory depression and potential addiction, are important factors that plague the safety of clinical use and are an urgent problem for pharmacological researchers to address. Current research on analgesic drugs has evolved into different directions: de-opioidization; application of pharmacogenomics to individualize the use of opioids; development of new opioids with less adverse effects. The development of new opioid drugs remains a hot research topic, and with the in-depth study of opioid receptors and intracellular signal transduction mechanisms, new research ideas have been provided for the development of new opioid analgesics with less side effects and stronger analgesic effects. The development of novel opioid drugs in turn includes selective opioid receptor ligands, biased opioid receptor ligands, and multi-target opioid receptor ligands and positive allosteric modulators (PAMs) or antagonists and the single compound as multi-targeted agnoists/antagonists for different receptors. PAMs strategies are also getting newer and are the current research hotspots, including the BMS series of compounds and others, which are extensive and beyond the scope of this review. This review mainly focuses on the selective/biased/multi-targeted MOR/DOR/KOR (mu opioid receptor/delta opioid receptor/kappa opioid receptor) small molecule ligands and involves some cryo-electron microscopy (cryoEM) and structure-based approaches as well as the single compound as multi-targeted agnoists/antagonists for different receptors from 2019 to 2022, including discovery history, activities in vitro and vivo, and clinical studies, in an attempt to provide ideas for the development of novel opioid analgesics with fewer side effects.