Investigation On The Action Between The Immobilized α_1A-adrenergic Receptor And Quinazoline Compounds By Affinity Chromatography

The structural modification of small molecules drugs and the study of their interactions with specific protein are very important for clarifying the biological processes of drugs and developing the efficient new drug. As an important functional proteins in the body,α1A-adrenergic receptor is one of the major targets of cardiovascular disease drugs. Studies have shown that among the drugs,which have specific effects withα1A-adrenergic receptor, quinazoline functional group is one of the main structural features, this suggesting quinazoline functional group is one of the active functional groups. Accordingly, this paper focus on the design, synthesis of some kinds of quinazoline compounds and the studies of interaction withα1A-adrenergic receptor, to establish a new ideas of the founding of drug active ingredients based on the structure modification of drugs and the study with specific functional proteins.The study is important for the discovery and development of the active ingredients of the efficient new drugs.The work has three chapters. The author's main study as follows:l.Take 2-chloro-4-amino-6,7-dimethoxy quinazoline,Piperazine as the main raw material,By acylation, esterification, and other chemical reactions, Synthesis 15 quinazoline and piperazine derivatives,Detected by high performance liquid,Purity were all greater than 98%, Study found that the synthesized products had high yields and were purificatied and separatied easily by this method. and By IR, NMR and other methods to determine the target compounds. Two of them have not been reported.2.Obtainα1A-adrenergic receptor purified from rabbit cardiac muscle by affinity chromatography, immobilized them on macroporous silica, establishingα1A-AR biological chromatography.the stationary phase were characterized by Norepinephrine, phenylephrine, metaraminol, urapidil,The results showed that:the average capacity factor of these medicine in the stationary phase were:2.94,4.97,2.57,5.49,respectively.this shows that the immobilized receptor has the ability to identify the ligands,And study the retention time of phentolamine, norepinephrine, Tamsulosin inα1A-AR column within 7 days,The results showed that: the relative standard deviations of three drugs were 2.27%,3.31%,3.70%, The retention time of three drugs has no significant change, basically.this Show that the model can effectively maintain receptor biological activity, has the good stability and specificity characteristics, can be used for researching the interactions of receptor and drug,and the efficient screening medicine active ingredients in complex systems.3.We researched the retention behavior of 15 kinds of the synthesized quinazoline compounds in theα1A-adrenergic receptor column,the results show that:Compound 1, compound 2, compound 3, compound 4, compound5, compound 8, compound 9, compound 10, compound 11 all retained in theα1A-AR column,and Retention time were:11.23,6.48,23.88,9.87,7.11,11.46,3.81,3.72,4.05 min,respectively.And using Frontal Analysis to research the Binding sites and binding constant between immobilizationα1A-AR and these compounds,the Binding sites were:0.934,1.282,1.032,1.385,0.391,0.664,2.828,2.924,3.008×10-6/M,respectively:the binding constant were:1.027,0.573,2.177,0.738,1.770,1.904,0.139,0.135,0.140×104/M-1,,respectively.This shows that the receptor Chromatography model an be used to research the interaction between the receptor and drug online.