Virtual Screening Of μ-opioid Receptor Biased Agonists And Design、Synthesis Of μ、δ、κ-opioid Triple Agonists

Clinically used opioids such as morphine,buprenorphine,fentanyl,etc.are important drugs for the treatment of pain.Due to their serious adverse effects such as euphoria,physical dependence,respiratory depression and gastrointestinal disorders,which have caused drug abuse and even lethality,thus development of low toxic side effects and analgesic activity of opioids has always been the hot topic for researchers.The first chapter of this thesis gives a brief introduction to Computer-aided drug design methods（CADD）.The second chapter summarizes the research status of opioid receptor agonists.Combined with computer-aided drug design methods,it is applied to the discovery of new structural skeleton ofμ-opioid receptor bias agonists.The third chapter of this thesis focus on the virtual screening ofμ-opioid receptor bias agonists based on the CADD.On the bias of the reported PZM21 with bias activation and TRV130 in clinical phase III as a reference template for similarity search,we construct a pharmacophore model with a series of pyridine benzimidazolone compounds to screen the compound library obtained in the previous similarity search and use GOLD to perform molecular docking on the compound with a high pharmacophore matching value to investigate the binding mode.Then we select the screened molecules with high scores and use See SAR to predict binding affinity and use molecular dynamics simulation to analyze the stability ofμ-opioid receptor-small molecule complexes,and ultimate forecast the binding free energy ofμ-opioid receptor-small molecule complexes by MM-PBSA.Through these methods,the IBS database was screened layer by layer and finally 4 candidate molecules were obtained and preliminary activity tests were performed on these molecules.Among them,compounds 12 and 14 haveμ-opioid receptor agonistic activity(EC₅₀=2.261μM,EC₅₀=9.636μM),in addition,it was found that these two compounds also have agonistic activity onδ-opioid receptor(EC₅₀=2.636μM and EC₅₀=0.039μM)andκ-opioid receptor(EC₅₀=49.900μM and EC₅₀=5.616μM).It was observed that compound 15 only has agonistic activity on delta-opioid receptors(EC₅₀=2.412μM).In Chapter 4 of this thesis,based on the structure of theμ、κ、δ-opioid receptor triple agonist DPI-125 and drug fentanyl,the types I and IIμ、κ、δ-opioid receptor triple agonists were designed,and the synthetic routes of the two types of compound skeletons were explored.At present,Type I compounds can be obtained through five-step reactions such as reductive amination,protection of phenolic hydroxyl groups,Buchwald-Hartwig C-N coupling reaction,deprotection of phenolic hydroxyl groups and further reductive amination.At present,20 compounds have been synthesized and some of them have been tested for MOR/DOR/KOR calcium flux agonistic activity.The core structure 19 can activate MOR(EC₅₀=7.456μM)and DOR(EC₅₀=33.700μM),and the introduction of benzyl in the structural modification solves the problem of inability to activate KOR,compound 24 has the strongest DOR agonistic activity,with EC₅₀ of 0.085μMIn this thesis,a potentialμ-opioid receptor bias agonist was discovered through virtual screening.Theμ、κ、δ-opioid receptor triple agonists were designed and synthesized for the discovery of opioids that retain analgesic activity and reduce side effects provides new ideas.