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 i s 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.
