Adenosine A2A receptor antagonists for the treatment of cocaine addiction

描述（由申请人提供）：A2A腺苷受体（A2AR）的选择性拮抗剂被认为具有治疗成瘾性疾病的潜力，包括可卡因成瘾。该提案是一项I期STTR，旨在研究具有专利的新颖、有效、选择性和生物可利用的A2AR阻滞剂，用于治疗可卡因成瘾。它是由进行药物化学和化合物表征的Adenosine Therapeutics有限责任公司和弗吉尼亚大学（University of Virginia）博士实验室合作的。Wendy Lynch和Jay Hirsh，他们在大鼠/小鼠成瘾模型中研究了化合物。本提案的目的是从ATL的文库和正在进行的A2AR拮抗剂的合成化学项目中筛选化合物，通过评估以下两种治疗可卡因成瘾的候选药物：1)基于结合重组人和大鼠腺苷受体亚型的化合物的效价和选择性；2)评价铅化合物在耐多药mdck细胞中的通透性，作为血脑屏障通透性的筛选；3)评估大鼠口服生物利用度、药代动力学和脑脊液（CSF）水平；4)合成足量的两种候选药物，以支持啮齿类动物可卡因成瘾的两种模型。这些目标直接关系到国家药物滥用研究所的使命，即通过针对可卡因成瘾的药物开发，使科学的力量对药物滥用和成瘾产生影响。我们预计，在这些努力结束时，我们将确定1或2先导化合物，并验证A2AR受体作为治疗可卡因成瘾的靶标。我们的长期目标是将一种新的化合物投入临床试验。这种新化合物具有很高的治疗意义，具有很高的商业和社会价值，对酒精、安非他明和尼古丁等其他成瘾物质具有额外的潜在效用。

DESCRIPTION (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 novel, 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 laboratories 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 therapeutic 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 cells 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 that 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 therapeutic significance and would be of high commercial and social value, with additional potential utility towards other addictive substances such as alcohol, amphetamine and nicotine.