Biocatalytic Synthesis of Selective D1 Agonists

DESCRIPTION (provided by applicant): "Drug addition is a complex illness. It is characterized by compulsive, at times uncontrollable drug craving, seeking, and use that persist even in the face of extremely negative consequences." As a consequence of the extraordinary personal, social, and health care costs associated with this problem, effective drug abuse treatment has become a national goal. There is preclinical and clinical evidence to suggest that a potent and selective dopamine D1 agonist would provide effective treatment for reducing craving and potentially decreasing the recurrence of cocaine use once a subject ceases using the drug. Currently, there are a number of deficiencies that must be overcome with existing D1 agonist, including poor oral bioavailability, short half-life, lack of selectivity for D1 receptors, and genotoxicity. Despite significant work using conventional chemical synthetic methods, such compounds have not yet been identified. We propose utilizing novel combinatorial biocatalysis technology on known D1 agonists, which for the deficiencies stated above fail to meet the criteria for use in a clinical setting. This technology can rapidly produce unique derivatives of these lead molecules and permit a search of chemical diversity space previously explored by previous efforts. This approach will prepare and rapidly assess numerous compounds with unique substitutions that may culminate in the identification of commercially viable candidates for the treatment of cocaine abuse. PROPOSED COMMERCIAL APPLICATION: The proposed work affords a substantial opportunity for commercial success. The clinical proof of concept experiment in humans (13) indicates a high probability of marketability should a compound be identified that overcomes the current liabilities of known D, agonists (1). Our proposed research focuses on the discovery of a series of derivatives that may have superior water solubility, reduced systemic toxicity, and higher potency and selectivity for the D, receptor. Such compounds can be directly developed for use in the treatment of addiction.