一种针对可卡因的催化抗体可预防可卡因对大鼠的强化作用和毒性作用。
A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats.
作者信息
Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe R J, Almonte R, Woods J H, Landry D W
机构信息
Department of Anesthesiology, Columbia University, College of Physicians & Surgeons, 630 West 168th Street, New York, NY 10032, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10176-81. doi: 10.1073/pnas.95.17.10176.
Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nonaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.
长期以来，可卡因成瘾和过量使用一直缺乏特效治疗方法。为了提供一种新的治疗方法，我们使用可卡因水解为无毒、无成瘾性产物的过渡态类似物，诱导产生了高活性催化抗体单克隆抗体15A10。在可卡因过量使用模型中，单克隆抗体15A10以剂量依赖的方式保护大鼠免受可卡因诱导的癫痫发作和猝死；非催化性抗可卡因抗体则不能降低毒性。与加速催化作用一致，在接受单克隆抗体15A10和致死剂量可卡因的大鼠血浆中，水解产物芽子碱甲酯增加了10倍以上。在可卡因成瘾模型中，单克隆抗体15A10完全阻断了可卡因对大鼠的强化作用。单克隆抗体15A10特异性地阻断可卡因，不影响由乳汁或多巴胺再摄取抑制剂安非他酮维持的行为。这种人工合成的可卡因酯酶是一种经过合理设计的可卡因拮抗剂，也是一种具有药用潜力的催化抗体。
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