作用于DA/5-HT受体亚型的反式-4-(2-(4-(吡啶-2-基)哌嗪-1-基)乙基)环己烷-1-胺衍生物的设计、合成及生物活性评价

Design,synthesis and bioactivity evaluation of trans-4-(2-(4-(pyridin-2-yl)piperazine-1-yl)ethyl)cyclohexane-1-amine derivatives acting on DA/5-HT receptor subtypes

目的设计合成反式-4-(2-(4-(吡啶-2-基)哌嗪-1-基)乙基)环己烷-1-胺衍生物,进行体外DA/5-HT受体结合实验及肝微粒体代谢稳定性实验,评价其体外抗精神分裂症活性和初步代谢特性。方法以反式-2-(4-氨基环己基)乙酸乙酯盐酸盐为起始原料,经酰胺化、硼氢化钠还原、甲磺酰化反应,再与吡啶基哌嗪片段进行烷基化反应制备目标化合物。经药效靶点(D_(2)、D_(3)、5-HT_(1A)、5-HT_(2A)受体)、副作用靶点(H_(1)受体)结合实验(单浓度抑制率)进行体外活性初筛,确定优选化合物后,再进行体外受体亲和力(K_(i)值)复测及人、大鼠肝微粒体代谢稳定性测定。结果与结论共设计合成24个新化合物,其结构经ESI-MS、^(1)H-NMR确证。体外受体结合实验结果显示,化合物1p、1v对D_(2)、D_(3)、5-HT_(1A)、5-HT_(2A)受体均具有较强的亲和力(1p:K_(i)=0.40、0.43、61.00、3.80 nmol·L^(-1);1v:K_(i)=6.70、5.80、22.00、7.60 nmol·L^(-1));对副作用靶点H_(1)受体的作用较低(10μmol·L^(-1)下抑制率分别为81.2%、83.6%)。同时,1p在肝微粒体上的代谢较稳定(human:t_(1/2)=30.40 min,CL=45.60μL·min^(-1)·mg^(-1);rat:t_(1/2)=51.40 min,CL=27.00μL·min^(-1)·mg^(-1)),具有作为新型多靶点抗精神分裂症活性分子进一步研究的价值。

Schizophrenia is a serious and complex chronic neuropsychiatric disease,and the existing drugs can not effectively improve the cognitive function of patients.Compound A,cariprazine and compound B were used as lead structures in this study,and based on the principle of pharmacophore fusion and substitution,24 trans-4-(2-(4-(pyridin-2-yl)piperazine-1-yl)ethyl)cyclohexane-1-amine derivatives were designed and synthesized.The compounds were prepared from ethyl trans-2-(4-aminocyclohexyl)acetate hydrochloride by amidation,reduction,methanesulfonylation and alkylation with pyridinyl piperazine fragment.The anti-schizophrenic activity and preliminary metabolic characteristics were evaluated by DA/5-HT receptors binding test and liver microsomal metabolic stability test in vitro.The results showed that compounds 1 p and 1 v had strong affinity for D2/D3/5-HT1 A/5-HT2 A receptors(1 p:Ki=0.40,0.43,61.00,3.80 nmol·L^(-1);1 v:Ki=6.70,5.80,22.00,7.60 nmol·L^(-1)),and had low effect on side effect target H1(under 10μmol·L^(-1),the inhibitory rates were 81.2%and 83.6%,respectively).Meanwhile,the metabolism of 1 p on liver microsomes was relatively stable(human,t_(1/2)=30.40 min,CL=45.60μL·min^(-1)·mg^(-1);rat,t_(1/2)=51.40 min,CL=27.00μL·min^(-1)·mg^(-1)).Thus,compound 1 p has the value of further study as a new multi-target anti-schizophrenia active molecule.