Novel Atypical Dopamine Modulators as Cocaine Pharmacotherapies

NOVEL ATYPICAL DOPAMINE MODULATORS AS COCAINE PHARMACOTHERAPIES P.I.: Steven R. Childers, Ph.D., EncepHeal Therapeutics SUMMARYCocaine addiction is a serious neuropsychological condition with profound consequences on both the individual and society. However, at present there are no FDA-approved pharmaceutical treatments for cocaine addiction. The goal of this Discovery BPN project is to develop atypical compounds that bind to dopamine transporters (DAT) at different sites within DAT compared to cocaine. Such compounds may have the ability to block some of cocaineandapos;s behavioral actions without producing some of the major undesirable effects (e.g., motor stimulation, high reinforcement activity) produced by cocaine and other psychostimulants. Newly patented atypical DAT analogs based on the structure of modafinil have been developed by Dr. Amy Newmanandapos;s lab at the NIDA Intramural Research Program (IRP). Unlike cocaine, these atypical DAT compounds do not produce stimulant activity or increase extracellular dopamine in brain, but do block cocaine self-administration in rats without producing significant reinforcement on their own. EncepHeal Therapeutics has obtained an exclusive license to this technology and is prepared to further develop and commercialize it as potential pharmacotherapies to treat cocaine addiction.A Phase I SBIR project awarded to EncepHeal has successfully identified one modafinil analog, JJC8- 091, as a candidate for further development, using rodent models of cocaine self-administration to establish efficacy and reinforcement properties. This compound exhibited all the positive effects of an atypical DAT compound, but its low bioavailability and potential cardiac safety issues makes it problematic as a lead development candidate. An extensive SAR exists for these analogs, but this SAR was optimized for binding to DAT, not for optimizing for drug development issues like bioavailability and affinities at cardiac ion channels. EncepHeal and our colleagues at Wake Forest School of Medicine have all the biological and pharmacological expertise to characterize these atypical DAT compounds in animal models, including rats and non-human primates. But we lack the chemical and ADME expertise to generate the number of compounds that can address the liabilities of JJC8-091. This project will use the BPN contractors to establish a new SAR for these atypical DAT compounds, specifically addressing cardiac and ADME issues. The team at EncepHeal will characterize effects of these compounds in rodent and monkey models, thus providing the information necessary to establish efficacy and safety criteria to move a lead compound candidate forward into IND- enabling activities. Phase I will start by validating in vitro screening and in vivo rat behavioral procedures, then screen new compounds for efficacy and safety. The lead compound identified in Phase I will then proceed to Phase II for additional rat behavioral testing and tests of efficacy and reinforcement in non-human primates. If successful, the final studies in Phase II will be conducted by BPN contractors to establish IND-enabling criteria.NARRATIVECocaine addiction is a serious medical and social problem, yet there are no medications approved by the FDA to treat cocaine addicts. New approaches are needed to produce novel medications to reduce cocaine abuse. This project will develop novel compounds that act in unique ways in the brain to reduce craving for cocaine in addicts. !