Structure-activity Relationships And Optimization Of Diarylmethylpiperazine Opioid Receptor Mixed Agonists

Opioids analgesics,mainly selective agonists for ?-opioid receptor,are important clinical drugs.However,these drugs also have serious side effects such as respiratory depression,addiction and tolerance.Respiratory depression can be life-threatening for patients,addiction can cause drug abuse,and tolerance can reduce analgesic effect.It is of great significance to reduce or eliminate the above side effects while maintaining or improving the analgesic effect.A number of experimental data have shown that there is a mutual balancing between activation effects of opioid receptors.This balancing can be used to eliminate opioid side effects,and can be achieved with mixed opioid receptor agonists.Our research group mainly focuses on the research and development of diarylmethylpiperazine mixed opioid receptor drugs.BW373U86 is the first small molecule ? receptor agonist which was developed by Prof.Kwen-jen Chang.Based on the structure of BW373U86,a number of mixed agonists of ?/?/? opioid receptor were discovered.Further in vivo pharmacological study revealed that mixed agonists with ?>?~? activity can effectively reduce side effects of respiratory depression and addiction.Therefore,?/?/? opioid receptor mixed agonists are promising drug candidates for pain relief and detoxification.In this study,computer-aided drug design method was carried out with DPI-3290 as the starting point using computer-assisted strategies and methods in rational drug design.To establish models of activated human ?,?,and ? receptors,homology modeling was first performed based on a crystal structure of activated ? receptor.Three-dimensional quantitative structure-activity relationship(3DQSAR)analysis was performed for the known ligands.The obtained models of activated opioid receptors and ligand structures were then used in molecular docking study.For DPI-3290 analogues synthesized in our lab,their pharmacokinetic properties and interactions with the receptors were predicted with computational tools.These works provide clues potentially useful for future research and development of better diarylmethylpiperazine mixed opioid receptor agonists.Specifically,this thesis includes the following parts:In Chapter 1,based on the molecular targets and chemical structures,recent reports on smallmolecule opioids were summarized,and the summary of this study was described.In Chapter 2,ligand-based modeling methods were used to study the structure-activity relationship of the dibenzylpiperazin scaffold,and a comparative position analysis(CoMFA)model and a comparative molecular similarity index analysis model(CoMSIA)model were constructed.The ligand-based 3D-QSAR results were obtained,and hopefullye to provide some clues for the design of new high-activity opioid receptor agonists.In Chapter 3,the three-dimensional structures of human ?,?,and ? opioid receptor subtypes were constructed by using multi-template homology modeling,and were evaluated using the ramachandran plot by measuring the conformation of amino acid residues in the protein.The energy appraisal was carried out with PROSA software to evaluate if the models were in the Z-score area determined by experimental data in the PDB database.In Chapter 4,based on the constructed structures of activated human ?,?,? opioid receptor subtypes,receptor-based molecular docking docking was carried out to study the interactions between the receptors and ? receptor agonist BW373U86 or opioid receptor mixed agonist DPI-3290.The results would provide guidance and theoretical basis for further molecular design.In Chapter 5,several important pharmacokinetic(ADMET)parameters of a series of derivatives of DPI-3290 was predicated,get useful information for reducing side effects of the compounds.Molecular docking of the activated states of the human ?,?,and ? opioid receptor subtypes with the known active DPI-3290 analogues was also performed and patterns of ligand-receptor interactions were analysized.In Chapter 6,the research work carried out in the term of postgraduate was smmarized and the further prospect was put forward.