A NEW PRODRUG APPROACH TO ADDICTION TREATMENT

该应用程序的总体目标是开发一种新型的 前药系统，其中前药和催化(酶) 将其转化为活性药物的分子是共同设计的。我们 期望这种类型的系统将促进前药的使用 治疗的方法，并建议它可能提供优势在 药物滥用者的维持治疗。我们的具体目标是让恶魔- 诺拉明前药可制得非活性药物 接受过催化抗体治疗的个人 催化转化为诺拉姆。具体而言，建议(1) 合成诺拉姆的衍生物，这些衍生物被很好地吸收，但只有 缓慢地，如果可以的话，在体内转化为NORLAAM，(2)，证明 这些前体药物确实被吸收了，但在止痛试验中没有活性， (3)合成模拟前药过渡态的半抗原 转化成药物并将其与蛋白质结合形成免疫原， (4)使用这些免疫原。以产生能够 催化转化，(5)测定这些化合物的催化性能 抗体和-(6)选择最适合使用的抗体。在……里面 此外，我们还将探讨半抗原结构与 高选择性和高选择性催化抗体的研制 很强的催化活性；并证明了给药 前药和催化性抗体均可导致 诺拉明的药理有效水平。动物模型将会是 在建议的授权期内使用。最终的目标将是 开发一种适合人类使用的系统。的重要意义。 这项工作既在于改进对吸毒者的治疗方法，也在于改善使用 静脉注射海洛因和感染艾滋病的高危人群以及 在开发药物输送的新概念方面。尽管NORLAAM是 使用的药物，方法学也应该适用于药物 有待开发。拟议的工作涉及有机合成， 免疫学，免疫化学，反应动力学，代谢， 在动物体内的药代动力学和药理试验。

The overall objective of this application is to develop a new type of prodrug system in which both the prodrug and the catalytic (enzymatic) molecule which converts it to active drug are designed together. We expect that this type of system will facilitate the use of the prodrug approach to therapy and suggest that it may offer advantages in the maintenance treatment of drug abusers. Our specific aim is to demon- strate that a prodrug of NORLAAM can be made which is inactive except in individuals who have been administered a catalytic antibody which catalyzes the conversion to NORLAAM. Specifically it is proposed to (1) synthesize derivatives of NORLAAM which are well absorbed but are only slowly, if at all, converted to NORLAAM in vivo, (2), demonstrate that these prodrugs are indeed absorbed but inactive in tests for analgesia, (3) synthesize haptens which mimic the transition state for the prodrug to drug conversion and conjugate them to proteins to make immunogens, (4) use these immunogens. to generate monoclonal antibodies which can catalyze the conversion, (5) determine the catalytic properties of these antibodies and-(6) select those which are best suited for' use. In addition, we will explore the relationship between hapten structure and the' development of catalytic antibodies with high selectivity and strong catalytic activity; and demonstrate that the administration of both prodrug and catalytic antibody results in the attainment of pharmacologically effective levels of NORLAAM. Animal models will be used in the proposed grant period. The eventual goal will be the development of a system suitable for use in humans. The significance of the work lies in both improving treatment methods for addicts who use intravenous heroin and who are at high risk for contraction of AIDS and in developing a new concept in drug delivery. Although NORLAAM is the drug to be used, the methodology should also be applicable to drugs yet to be developed. The proposed work involves organic synthesis, immunology, immunochemistry, reaction kinetics, metabolism, pharmacokinetics and pharmacological testing in animals.