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.