| By use of the design strategy of the medicine chemistry,to search for new therapeutic agents for the treatment of central nervous system disorders such as schizophrenia and other related diseases,this dissertation focused on design,synthesis and bio-evaluation of drug molecules based on the multi-receptor and sigma-1receptor,respectively.Firstly,on the basis of our previous work,we developed the work of the design,synthesis and bio-evaluation of multi-receptor antipsychotics.Schizophrenia is serious and chronic disabling disease afflicting nearly 1% of the general population,which can be relieved but cannot be cured.Although typical antipsychotics are effective in reducing positive symptoms,they are slowly fading out of first-line clinical medication because of their major side effects,such as extrapyramidal symptoms(EPS).Multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics.They simultaneously targeting dopamine D2 and 5-HT receptors,especially the 5-HT1 A and 5-HT2 A receptors.They not only effectively treat the positive symptoms of schizophrenia,but also may reduce negative symptoms and cognitive deficits in patients with fewer EPS.Because of they act on a wider spectrum of receptors,including 5-HT2 c,α1 and H1 receptors,they trigger many other adverse events,including weight gain and glucose and lipid abnormalities and QTc prolongation.Therefore,the discovery of safer and more effective multi-recepoter antipsychotic medications that effectively treat all aspects of the disease is tremendously important.On this basis,tow series of benzisoxazole derivatives: fused heterocyclicbenzisoxazoles and 6-hydroxypyridazinone benzisoxazoles,96 compouds have been designed and synthetized.In vitro receptor binding studies,fifiteen compounds exhibited good affinities for certain receptors(D2,D3,5-HT1 A,5-HT2 A,5-HT6 and 5-HT7 receptors)and combined with low affinities for the H1,5-HT2 C and adrenergic α1 receptors.In vivo test,nine compounds exhibited a high cataleptic threshold,five compounds did not block hERG channel and showed safety in acute toxicity study.Besides,compound 48 showed good stability in liver microsomes,transmembrane transport ability,and favorable pharmacokinetic profile in SD rats.In this part,the most effective compound 48 exhibited good affinities for the multi-receptor(D2,D3,5-HT1 A,5-HT1 A,5-HT6 and 5-HT7),with potential antipsychotic activities,good safety and favorable pharmacokinetic properties.These profiles suggest that compound 48 may be a member of a novel class of mutli-receptor candidate drugs for treatment of schizophrenia.Sigma(σ)receptor was recognized as new receptor subtype of the opioid family,molecular biology of the sigma receptor has been intensively studied,and it has a wide range of biological functional activities.The σ1 receptor plays a key role in human physiology,as an endoplasmic reticulum chaperone,it is not only involved in the regulation of calcium signaling,but also participates in the regulation of the activity of various ion channels and G protein coupled receptors.The ligands of σ1 receptor have potential therapeutic effects in a variety of disorders,including neurodegenerative diseases,mental disorders and neuropathic pain.The follow part of this paper mainly studies the design,synthesis and bio-evaluation of novel σ1 receptor ligands,by use of the 6-hydroxypyridazinone framework,a new series of potent σ1 receptor ligands was prepared.In vitro receptor binding studies,12 compounds revealed high σ1 receptor affinity and good excellent selectivity over σ2 receptor.In addition,functional activity of compounds was evaluated using phenytoin and indicated that these compounds were σ1 receptor antagonist.In summary,160 novel compounds targeting the multi-receptor and sigma-1 receptor have been designed and synthesized,severl scaffolds with potent activities have beenidentified.All the discussed works will be a good foundation for the developing new new drug with independent intellectual property rigths. |
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