The advent of combinatorial libraries composed of literally tens of millions of compounds in formats permitting the rapid identification of individual compounds offers an unprecedented opportunity for the development of new, highly active and exquisitely selective medications. While the three known opioid receptors (mu, delta and kappa) all regulate the perception of pain, they each differ in the type of pain inhibited, the non-analgesic functions mediated by these receptors, and their drug abuse potential. The well-characterized properties and differences in these three related receptors and the availability of receptor specific in vitro assay systems are ideally suited for exploitation by the combinatorial methods that have been developed by the principal investigator's laboratory. The nine different combinatorial libraries tested in the previously funded efforts have enabled the identification of over 30 new opioid receptor specific compounds, many of which were unlikely to have been identified by any other available methods. Of the compounds identified, approximately 75% were found to be agonists. A number of these compounds have been examined for in vivo activities and one of them, a highly active kappa selective agonist, has been tested in a primate model. There are now more than 40 different low molecular weight heterocyclic, acyclic, peptidomimetic and peptide combinatorial libraries available at the applicant organization. These will greatly facilitate the further identification and development of new opioid ligands as analgesics having central or peripheral agonist or antagonist activities. The libraries available for testing now include 350 million peptides, 30 million peptidomimetics and over 4 million low molecular weight acyclic and heterocyclic compounds, including indole-imidazoles, quinazolinones, and bicyclic guanidines. The focus of the proposed work will be to use these libraries, as well as libraries of globally fluorescent compounds, to identify agonists and antagonists of the mu, delta and kappa opioid receptors as therapeutics for the management of pain and the amelioration of cravings associated with addiction.
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