Sterling G H, Doukas P H, Sheldon R J, O'Neill J J
Department of Pharmacology, Hahnemann University School of Medicine, Philadelphia, PA 19102-1192.
Biochem Pharmacol. 1988 Feb 1;37(3):379-84. doi: 10.1016/0006-2952(88)90202-x.
Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of administration, dose-response relationships, and time to effect.
梭曼可不可逆地抑制乙酰胆碱酯酶，导致乙酰胆碱（ACh）蓄积，这是其产生诸多毒性作用的原因。目前的治疗方法包括：（1）阿托品，一种毒蕈碱受体阻滞剂；（2）氯解磷定（2-PAM），一种酶复活剂；（3）用氨基甲酸盐保护酶。然而，尚未找到完全令人满意的治疗方案，主要原因是老化过程迅速。在本研究中，对已知在体外抑制ACh合成的化合物与阿托品和2-PAM联合进行了评估，以评估它们在保护大鼠免受梭曼毒性方面的潜在效用。乙酰去甲半胆碱（100微克/千克，脑室内注射，在梭曼给药前30分钟），一种体外高亲和力胆碱摄取（HAChU）和胆碱乙酰转移酶（ChAT）活性的抑制剂，增强了阿托品和2-PAM的保护作用，降低了梭曼给药后最初2小时内的死亡率。N-羟乙基萘基乙烯基吡啶（NHENVP），一种季铵型ChAT抑制剂（1.7微摩尔/千克，肌肉注射），使梭曼导致的总体死亡率从80%显著降低至20%。该化合物在梭曼给药前2 - 3分钟给药时最有效，且仅通过肌肉注射途径有效。N-烯丙基-3-奎宁环醇，一种有效的HAChU抑制剂（1微摩尔/千克，肌肉注射），是所评估的最有效的奎宁环类似物，也降低了24小时内的死亡率百分比。与NHENVP不同，它在梭曼给药前30 - 60分钟给药时最有效。数据表明，体外破坏突触前ACh合成的化合物可能在治疗有机磷中毒方面有效。结果显示了所研究化合物之间有趣的差异，并为设计抗梭曼毒性的保护剂提供了见解。这些发现进一步强调了研究这些化合物的结构活性和药代动力学特性的必要性，即比较给药途径、剂量反应关系和起效时间。
