Bioactivity Study Of Analogues Of ?₁ Receptor Agonist SA4503 And New 2-cyclohexenone Derivatives

The sigma-1 receptors are widely distributed in the central nervous systems,peripheral tissues,and some tumor cell lines.Sigma-1 receptor and its ligands are associated with many pharmacological effects.They play important roles in the onset and treatment of many diseases.1-(3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride(SA4503)is a kind of N,N'-diaromatic alkyl piperazine Sigma-1 receptor agonist,with a 100-fold higher affinity for the ?1 receptor than that for ?2 receptor.SA4503 can significantly enhance extracellular acetylcholine levels and doesn't produce striatum cholinergic side effects.It has many pharmacological effects.At the present,the phase II clinical research on the application of antidepressant and neuroprotection of SA4503 has been completed.Although SA4503 is a good drug for depression and post-stroke recovery,its structure-activity relationship and treatment effect on other diseases still needs further research.Based on the lead structure of SA4503 and principle of rational drug design,we synthesized 15 N,N'-disubstituted piperazine compounds and 7 hydrochlorates of them.All of the hydrochlorates were tested for their protective effects on hypoxia/hypoglycemia-induced impaired vascular endothelial cells.Among of them,only compound A-VIII obviously increased the cell viability of human umbilical vascular endothelial EA.hy926 cells,but no apparent relationship between dose and activity was observed.Meanwhile,we tested the in vitro proliferation inhibition activities against five human tumor cell lines of six of the hydrochlorates.Among of them,both compound A-I and A-III had certain proliferation inhibition effects on the five cell lines.Compound A-II had obvious inhibition effect on the proliferation of MCF-7 cells,and its IC50 was similar with positive control group.However,the SAR and dose-activity relationship of these compounds need further study.Furthermore,in the previous studies,our group had developed a new method to synthesize new 2-cyclohexenone derivatives and isobenzofuran derivatives catalyzed by microwave-assisted acid.On that basis,we synthesized 11 new 2-cyclohexenone derivatives and 11 isobenzofuran derivatives.10 of the 2-cyclohexenone derivatives and 9 of the isobenzofuran derivatives were tested for their in vitro proliferation inhibition activities against.five human tumor cell lines.All of the tested cyclohexenone derivatives exhibited certain inhibition effects on the proliferation of one or more cell lines.Compound 23b had a significantly inhibition effect on the proliferation of MCF-7 cell lines,which was 2-fold stronger than that of the positive control group,and it may be expected to become a good lead compound against breast cancer.Besides,compound 23g exhibited a similar proliferation inhibition effect on MCF-7 cell lines.In addition,6 of the tested isobenzofuran derivatives also exhibited certain inhibition effects on the proliferation of one or more cell lines.