Design And Synthesis Of A Series Of Dopamine D₃ Receptor And Study On The Synthesis Of N-Substituted Phenylpiperazine Compounds

Dopamine is a kind of important neurotransmitter in the brain.Dopaminergic system is closely related to neuropsychiatric diseases.The D3 receptor belongs to D2 class subtype,mainly in the midbrain margin system.The synthesis of dopamine and The release of neurons plays a key role in regulating movement,learning and memory,and many other functions.At present,pharmacological studies have used D3 receptors as a potential target for the treatment of central diseases such as depression,paclitaxel,and drug dependence.Therefore,the design and synthesis of dopamine D3 receptor ligands with high affinity and high selectivity have become one of the hotspots of drug chemists.The paper is divided into two parts:the first part,design,synthesis and pharmacokinetics of dopamine D3 receptor ligand;the second part,the synthesis of N-substituted phenylpiperazine compounds.The first part of the thesis is divided into two chapters:In the first chapter,the progress of dopamine D3 receptor ligand in recent years were reviewed.In the second chapter,based on the structure-activity relationship analysis of known dopamine D3 receptor ligand with high affinity,the compounds of BP897 and RGH1731 were used as the lead compounds,and the basic principles of drug design such as bio-isotope and stitching principle were used to design the substituted phenylpiperazine and 3-(1-piperazinyl)-1,2-Isothiazole,and the role of dopamine D3 receptor protein was verified by molecular docking.Secondly,the author designed the synthetic route with easy feed,simple operation and high yield,and optimized the key reaction routes.The 25 target compounds were synthesized and no reported in the literature.All the products were analyzed by 1H-NMR,13C-NMR And MS structure confirmation.The results showed that six compounds had higher affinity for dopamine D3 receptors,and the compounds were screened by radioligand binding experiments.Finally,the author simulated the ADMET property test.The results showed that the above six compounds were within the normal range through the blood-brain barrier,passive intestinal absorption,water-soluble,hepatotoxicity,CYP2D6 enzyme binding,P4502D6 enzyme inhibition and plasma protein binding,Which indicates that these compounds have certain advantages in pharmacokinetics,and provide some reference for the development of late related drugs.In the second part of the thesis,the synthesis route of N-substituted phenylpiperazine compounds was studied.On the basis of the reference literature,a process route for the preparation of N-substituted phenylpiperazine hydrochloride by free-solvent homogeneous reaction of substituted aniline and N,N-dichloroethylamine hydrochloride at high temperature was developed,The effects of reaction solvent,ratio of raw materials,reaction temperature and time on the experimental results were investigated.The process has the advantages of simple operation,less waste and less reaction time,and is suitable for industrial production.The optimum conditions for the determination of N-substituted phenylpiperazine hydrochloride by the method of single factor study were as follows:the detection wavelength was 249 nm,The mobile phase consisted of acetonitrile:KH2PO4 buffer(pH = 3.5)= 50:50,flow rate 0.8ml · min-1,injection volume 20?l.The method is simple,reproducible,accurate and reliable,suitable for the quality control of N-phenylpiperazine hydrochloride.