A NEW PRODRUG APPROACH TO ADDICTION TREATMENT

本申请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被设计在一起。我们 预期这种类型的系统将促进前药的使用 治疗方法，并建议它可能提供的优势， 药物滥用者的维持治疗。我们的目标是- 可以制备NORLAAM前体药物，该前体药物除了 已经施用催化抗体的个体，所述催化抗体 催化转化为NORLAAM。具体而言，建议（1） 合成吸收良好但仅 缓慢地，如果有的话，在体内转化为NORLAAM，（2），证明， 这些前药确实被吸收但在镇痛试验中无活性， (3)合成模拟前药过渡态的半抗原 药物转化和蛋白质结合来制造免疫原， (4)使用这些免疫原。产生单克隆抗体， 催化转化，（5）确定这些催化剂的催化性能 抗体和（6）选择最适合使用的那些抗体。在 此外，我们将探讨半抗原结构与 开发具有高选择性的催化抗体， 强的催化活性;并证明， 前药和催化抗体都导致实现 NORLAAM的有效水平。动物模型将 在拟议的补助金期间使用。最终目标将是 开发适合人类使用的系统。的意义 这项工作在于改善吸毒成瘾者的治疗方法， 静脉注射海洛因和感染艾滋病的高危人群， 开发一种新的药物输送概念。虽然诺兰是 药物使用，该方法也应适用于药物尚未 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， 在动物中的药代动力学和药理学测试。

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.