This is a proposal to design and synthesize a group of novel compounds that can bind cocaine and catalyze its hydrolysis. The compounds are expected to be non-toxic and to bind cocaine and hydrolyze it with specificity. Since this is a novel approach to the cocaine problem, a variety of structures are suggested that can bind cocaine by interacting with its benzoyl group, its tropane skeleton, and its nitrogen atom. The catalysts that are simplest to prepare will be examined first, but the more complicated structures are likely to be more effective and more specific for cocaine. The catalysts proposed are not proteins, but are enzyme mimics using some sugar derivatives for part of their cocaine binding. The relatively small structures proposed have the advantage of """"""""small molecules"""""""" as medicinal agents. It should be possible to administer them in drug-release depots, and also to administer them both orally and by injection. Since they are not proteins, they will almost certainly not be antigenic. Thus repeated treatment should be possible. The proposed structures take advantage of previous work of the principal investigator in which certain esters, but not yet cocaine, were catalytically hydrolyzed with rate accelerations of 14,000,000. It is proposed that catalysts designed for cocaine hydrolysis, if they achieve such accelerations, will be useful in treating cocaine addiction and also in treating cocaine intoxication from overdose. In this proposal only the chemical studies to establish the effectiveness of these catalysts in hydrolyzing cocaine under physiological conditions - including with added serum - will be studied. If some highly effective catalysts are developed, subsequent work for which no funds are requested at this time will be devoted to the animal and human trials needed to establish the new catalysts as useful medicinal agents for the treatment of cocaine addiction and cocaine poisoning.
