抗有机磷酸酯药物的合成及其构效关系的研究

本文报道一类双吡啶季铵盐化合物,对抗小鼠有机磷酸酯化合物中毒有效,其中一些化合物的抗毒效价超过了文献报道的HI-6,HGG-42的水平。为探讨其构效关系,用EHMO方法计算了23个化合物的分子轨道指数,从中发现吡啶环Ⅱ和羰基可能是化合物的活性部位,影响抗毒作用的因素有二个,并再次设计合成了二个新化合物,量化计算预测的抗毒效价与药理结果一致。化合物与胆碱N受体结合有较强的选择性,根据计算,提出了其可能的作用模式,推测N受体活性部位除有文献报道的阴离子部位、亲酯中心、疏水区域外,还可能有轨道作用部位。

STUDIES ON ANTIDOTES FOR ORGANOPHOSPHATE POISONING SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF BISPYRIDINIUM SALTS

A new series of asymmetric bispyridinium salts were synthesized as antidotes against organophosphate poisoning and the prophylactic activities against organophosphate poisoning in mice were reported. The results indicate that when R were various ketone groups at the position 3 on the second pyridine ring, the com pounds showed significient activities and some of them possesed more potent antidotal action than those of HI-6 and HGG-42; while R were substituted at position 4, the activities were lost. When R were amide or alcohol group, their activities were diminished.In order to search for structure-activity relationship of these compounds the molecular orbitals of twenty-three bispyridinium salts were calculated by means of the EHMO method on VAX-11/780 computor. It was suggested that the pyridinium ring Ⅱ and the carbonyl group were active sites in these compounds. Two MO indices, arrangements of signs of coefficients in the LUMO of atoms at pyridinium ring Ⅱ (denoted by SCLAP) and the reduced charge of the LUMO on the carbonyl carbon atom (denoted by RC), were found to be closely related to their antidotal activities. The former showed the possibility of a symmetry-allowed or symmetryforbbiden interaction of frontier orbitals with receptors and the latter represented the electrophilic ability of carbonyl carbon atom. All of seventeen active compounds showed the A type arrangements of the SCLAP and higher RC(0.6215～0.9787), while the other seven inactive compounds exhibited B type arrangements of the SCLAP or lower RC. This relationship has been confirmed by further design and synthesis of two new compounds, so the above SAR may be used as reference to search for more potent new antidotes: Preliminary pharmacological experiments indicate that these compounds had Iittle inhibiting action on acetylcholinesterase (AchE)and no reactivating activity of phosphorylated AchE, but they showed antimuscarinic and more potent antinicotinic action, including both ganglionic blocking and neuromuscular blocking activities. The active compounds could be combined with N-receptor firmly even at tho concentration of 10^-7 tool. Three sites (anionic, csterphilic and hydrophobic), existing in the active portion of N-receptor, had been reported in literatures and now the fourth active site with A type arrangement of the HOMO may be present in N-receptor and a possible schematic diagram of interaction of bispyridinium salts with N-receptors was suggested.