The Discovery And Modification Of Quinazoline Derivatives As5-HT_2AAntagonists

Serotonin5-HT2A receptor belongs to GPCR superfamily and is wildly expressed in both central nervous system (CNS) and periphery tissues, monitoring various functions of organisms in human body. Serotonin5-HT2A receptors in CNS regulate excitation of nerves, human behavior,as well as learning and mood.Though excitation of5-HT2A receptor in CNS causes hallucination which is the mechanism of drug addictionlike cocaine and amphetamine derivatives, researches mainly focus on the antagonism of5-HT2A receptor. A great many atypical antipsychotics feature in their antagonism effects both on dopamine D2receptor and serotonin5-HT2A receptor with a relatively high affinity for5-HT2A (the "5-HT2A/D2hypothesis of atypicality"). This feature results in less extrapyramidal system (EPS) adverse effects which distinguishes atypical antipsychotics from typical antipsychotics. The selectively antagonism of5-HT2A receptor in CNS can also be a treatment for anxiety and sleep disorder (insomnia). Researches reported also indicate that5-HT2A receptor antagonists may be a treatment for addiction for their capability of regulating the release of dopamine in the brain. Besides, they showed more potential than dopamine receptor antagonists for attenuating craving and relapse of patients.Since their capability of treating so many diseases, development of5-HT2A receptor antagonists are of significant importance.The major structure profiles of both on sail and on studied5-HT2A antagonists are:a) tricycles; b) phenylpiperazine derivatives with two different aromatic rings linked by an aliphatic chain with a protonated N as shown below. Structure features of the tricycles are similar to atypical antipsychotics developed in the1950s where an aliphatic chain with a protonated N is attached to the tricycles core. Another type of5-HT2A receptor antagonists which named phenylpiperazien, features in various aromatic rings attached to both sides of a linker with a protonated N, aripiprazole is a representative of this class of agents.However, both of the tricycles and phenylpiperazine have their owndistinctiveside effects that cannot be overcome due to their structural features. For tricycles antidepressants, they have antagonistic effect on periphery cholinergic receptors causing atropine-like effect. Also, they cause lower blood pressure and inhibit various cardiovascular reflexes. For phenylpiperazine atypical antipsychotics, Haloperidol, Risperidone and Aripiprazole are all reported causing headache, insomnia, exaltation and anxiety in clinical trials. These adverse effects are correlated to the skeleton feature of these compounds. In this regard,5-HT2A receptor antagonists with novel structure profiles shall be developed. Here we report the discoverer of novel5-HT2A receptor antagonists through CADD method and rational drug design. SAR of this series of compounds was discussed via docking and QSAR. And finally, a5-HT2A receptor antagonist with Ki value of45.77±8.67nM was identified. These efforts laid the foundation for further work of developing novel, highly active5-HT2A antagonist.Divided into three sections, this thesis includes:a) The homology modeling of serotonin5-HT2A receptor,followd by receptor-based pharmacophore was built. Using this pharmacophore as a query, virtual screening was carried out and several hits were picked for the first round of bioassays.According to the results, compounds with relatively high activity were selected as lead compounds for further modification and drug design, b) Synthesis of the designed compounds, c) Second round of bioassay of the synthetics followed bydata analyses and QSAR disussion. Finally, novel quinazoline5-HT2A antagonists with high affinity were discovered.