Design,Synthesis And Activity Evaluation Of The Arylpiperidine(Piperazine) Compounds As Multitarget Antischizophrenic Drugs

Schizophrenia is a chronic and serious disease of central nervous system,affecting about 1%of the population,causing serious physical and psychological harm to patients,brings heavy burden to their families and society.At present,the antipsychotics drugs in clinic mainly include typical,atypical and the new generation antipsychotic drugs.Although these drugs showed a certain efficacy for schizophrenia,there still exist different defects in some aspects,such as less or not effective to the negative symptoms and cognitive impairment,as well as some side effects associated with treatment,such as extrapyramidal side effect,hyperprolactinemia,weight gain,QT interval elongation and so on.So far,there was no drug in clinic achieved satisfactory results in treatment of schizophrenia,and the treatment of negative symptoms and cognitive impairment of schizophrenia remains a challenge.Therefore,researching and developing mutli-receptor antipsychotic medicines with better efficacy and safety remains an important clinical need.Based on this background,in this dissertation,a series of new aromatic piperidine(piperazine)derivatives was designed and synthesized by means of the multi-target drug design strategies and combined with the therapeutic characteristics of the multi-target antischizophrenic agents and previous research of our group.Those compounds were evaluated in vitro,and the optimized compounds were subjected to further assessment in vivo,including the animal models,acute toxicity and pharmacokinetics.The final candidate compound exhibited better anti-schizophrenic activity,low liabilities for side effects,and also exhibited favorable cognitive enhancement.The main research contents are as follows:Firstly,five types of new aromatic piperidine(piperazine)derivatives(114compounds)have been designed and synthesized,and the structure of those compounds was confirmed by NMR(Nuclear Magnetic Resonance)and MS(Mass Spectrometry).Secondly,106 compounds were screened based on the D2,5-HT1A and 5-HT2A receptors.Among them,19 compounds showed good affinities for the three receptors.Then,further screening was carried out based on the cognition-related receptors(D₃,5-HT₆ and H₃)and side effect-related receptors(?₁,5-HT_2C and H₁).The structure-activity relationship(SAR)was demonstrated and 9 compounds were selected as preferred compound.Thirdly,several animal models of schizophrenia were constructed and the anti-schizophrenic activity of the preferred compounds were evaluated by those models.The results of apomorphine-induced hyperlocomotion,MK-801-induced hyperactivity and catalepsy test show that those preferred compounds have good in vivo activity against schizophrenia.Among them,compounds HKB-29,HKB-46 and HKB-53 exhibited better anti-schizophrenia activity and higher therapeutic index.In addition,the primary safety evaluation of the 9 preferred compounds was conducted by acute toxicity test.The LD50values of HKB-29,HKB-46 and HKB-53 exceeded 2000 mg/kg,with no apparent side effects and higher security.Thus,compounds HKB-46 and HKB-53 were chosen for the novel object recognition study,and the results showed that HKB-46 and HKB-53displayed pro-cognition properties.Finally,the pharmacokinetic properties of HKB-53 were measured in rats;the results showed that HKB-53 has favorable pharmacokinetic characteristics in SD ratsIn conclusion,a series of new aromatic piperidine(piperazine)derivatives have been designed and synthesized,and their biological activities and SAR were evaluated in vitro and in vivo.Among them,compounds HKB-46 and HKB-53 and other preferred compound showed better multi-receptor activity against schizophrenia,with the potential to be developed as the multi-target anti-schizophrenia drug.All the above researches laid a good foundation for developing novel anti-schizophrenia drugs with independent intellectual property rights.