Cocaine addiction is a serious neuropsychological condition with profound consequences on both an individual and society. However, at present there are no FDA-approved pharmaceutical treatments for cocaine addiction. One potential solution is to develop inhibitors at biogenic amine transporters (especially the dopamine transporter [DAT]) that are structurally dissimilar to cocaine and could potentially bind to different sites compared to cocaine within DAT. Such inhibitors may have the ability to block some of cocaine's behavioral actions without producing some of the major undesirable effects (e.g. motor stimulation; high reinforcement activity) produced by cocaine and other cocaine-like DAT inhibitors. Modafinil (Provigil), a weak DAT inhibitor that is used clinically (at high doses) for treatment of narcolepsy, has been tested in clinical trials for cocaine addiction treatment with mixed results. In particular, the weak potency, low efficacy and unfavorable side effects limit the potential utility of modafinil itself as a cocaine pharmacotherapy. Newly patented modafinil analogs developed by Dr. Amy Newman's lab at the NIDA Intramural Research Program (IRP) are more potent than modafinil at DAT, and preliminary behavioral data show that these analogs block cocaine self-administration in rats without producing significant reinforcement or motor stimulation on their own. After winning a national competition sponsored by the NIH to create a company around a specific NIH invention, 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. The proposed research in this Phase I SBIR project will focus on characterizing drug candidates from an in-licensed library of novel modafinil analogs produced by Dr. Newman at the NIDA IRP. These studies will achieve the following: 1) Determine in vitro metabolism of selected modafinil analogs in liver microsomes, CYP induction, and cardiac safety; 2) Determine in vitro radioligand binding affinities at human biogenic amine transporters (hDAT, hSERT, and hNET), and perform preliminary quantification of pharmacokinetic (PK) properties after in vivo administration of analogs in rats; 3) Examine blockade of cocaine self-administration in rats on progressive-ratio schedules, and intrinsic reinforcement properties in rats on a fixed-ratio drug discrimination assay. All of the data generated by this SBIR project will be combined with complementary data from the NIDA IRP to provide a complete preclinical description of lead drug candidate(s) to be commercialized by EncepHeal for further development as a medication agent for cocaine addiction. These compiled data will assist EncepHeal Therapeutics in choosing a single lead compound for Phase II evaluation of efficacy in non-human primates, other IND-enabling tests, and future commercialization.
Cocaine addiction is a serious medical and social problem, yet there are no medications approved by the FDA to treat cocaine addicts. Modafinil (Provigil), currently marketed to treat sleep disorders, has been suggested as a potential treatment agent for cocaine addiction, but its weak potency has limited its usefulness in the clinic. This project will develop novel modafinil analogs as medications to reduce craving for cocaine in human addicts.
