Adenosine A2A receptor antagonists for the treatment of cocaine addiction

描述(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障碍的潜力，包括可卡因成瘾。这项提案是第一阶段STTR，旨在研究专有的新型、有效、选择性和生物可用的A2AR阻滞剂，用于治疗可卡因成瘾。这是腺苷治疗公司和弗吉尼亚大学温迪·林奇博士和杰伊·赫什博士的实验室之间的合作，腺苷治疗公司在那里进行药物化学和化合物表征，在那里，化合物在大鼠/小鼠成瘾模型中进行研究。这项建议的目的是从ATL的文库和正在进行的A2AR拮抗剂合成化学计划中筛选化合物，以确定治疗可卡因成瘾的两种候选药物，方法是：1)根据与重组人和大鼠腺苷受体亚型结合的化合物的效力和选择性；2)作为血脑屏障通透性的筛选，评估先导化合物在MDR-MDCK细胞中的渗透性；3)评估大鼠的口服生物利用度、药代动力学和脑脊液(CSF)水平；以及4)合成足够数量的两种治疗候选药物，以支持两种啮齿动物模型的可卡因成瘾。这些目标与国家药物滥用问题研究所的使命直接相关，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，在这些努力的结束时，我们将鉴定1到2种先导化合物，并验证A2AR受体作为治疗可卡因成瘾的靶点。我们的长期目标是将一种新化合物带入临床试验。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.