Adenosine A2A receptor antagonists for the treatment of cocaine addiction
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310 FOURTH STREET NE, SUITE 201, CHARLOTTESVILLE, VA, 22902
AbstractDESCRIPTION (provided by applicant): Selective antagonists of A2A adenosine receptors (A2AR) are thought to have potential for the treatment of addictive disorders, including cocaine addiction. This proposal is a phase I STTR to investigate proprietary nov el, potent, selective and bioavailable A2AR blockers for the treatment of cocaine addiction. It is collaboration between Adenosine Therapeutics, LLC, where medicinal chemistry and compound characterization are conducted, and University of Virginia laborato ries of Drs. Wendy Lynch and Jay Hirsh, where compounds are investigated in rat/mouse models of addiction. The Aims of this proposal entail screening compounds from ATL's library and ongoing synthetic chemistry program on A2AR antagonists to identify two t herapeutic candidates for the treatment of cocaine addiction by assessing: 1) the potency and selectivity of compounds based on binding to recombinant human and rat adenosine receptor subtypes; 2) evaluating the permeability of lead compounds in MDR-MDCK c ells as a screen of blood-brain barrier permeability; 3) assessing oral bioavailability, pharmacokinetics and cerebral spinal fluid (CSF) levels in rats; and 4) synthesizing adequate quantities of two therapeutic candidates to support two models of cocaine addiction in rodents. These objectives directly relate to the mission of the National Institute on Drug Abuse, which is to bring the power of science to bear on drug abuse and addiction, by targeting drug development for cocaine addiction. We anticipate t hat at the conclusion of these efforts we will identify 1 or 2 lead compounds and validate the A2AR receptor as a target for treating cocaine addiction. Our long term goal is to bring a new compound into clinical trials. Such a new compound has high therap eutic significance and would be of high commercial and social value, with additional potential utility towards other addictive substances such as alcohol, amphetamine and nicotine.
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