Adenosine A2A receptor antagonists for the treatment of cocaine addiction

腺苷 A2A 受体拮抗剂用于治疗可卡因成瘾

• 批准号: 7155456
• 负责人: JAYSON MICHAEL RIEGER
• 金额: $ 10.48万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155456
• 关键词: Adenosine; Adenosine A2A Receptor; Alcohols; Amphetamines; Animals; Behavioral; Binding; Bioavailable; Biological Availability; Blood - brain barrier anatomy; Brain; Cerebrospinal Fluid; Cerebrum; Clinical Trials; Cocaine; Cocaine Dependence; Collaborations; Disease; Drug Kinetics; Drug abuse; Goals; Human; Infusion procedures; Institutes; Intraperitoneal Injections; Intravenous; Laboratories; Lead; Libraries; MDCK cell; Methodology; Methods; Mission; Modeling; Mus; Nicotine; Oral; Parkinson Disease; Permeability; Pharmaceutical Chemistry; Phase; Purinergic P1 Receptors; Rattus; Recombinants; Research; Rodent; Schedule; Science; Screening procedure; Self Administration; Small Business Technology Transfer Research; Social Values; Specificity; Sprague-Dawley Rats; Sucrose; Synthesis Chemistry; Testing; Therapeutic; Thinking; Universities; Ursidae Family; Virginia; addiction; base; drug development; male; mouse model; novel; programs; receptor; response

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.

描述（由申请人提供）：A2 A腺苷受体（A2 AR）的选择性拮抗剂被认为具有治疗成瘾性疾病（包括可卡因成瘾）的潜力。该提案是一项I期STTR，旨在研究用于治疗可卡因成瘾的专有新型、强效、选择性和生物可利用的A2 AR阻滞剂。这是腺苷治疗有限责任公司（Adenosine Therapeutics，LLC）与弗吉尼亚大学实验室（University of Virginia laboratories of Drs. Wendy Lynch and Jay Hirsh）之间的合作，在那里，化合物在大鼠/小鼠成瘾模型中进行了研究。该建议的目的是从ATL的文库和正在进行的A2 AR拮抗剂合成化学计划中筛选化合物，以通过评估以下来鉴定用于治疗可卡因成瘾的两种治疗候选物：1）基于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）评价先导化合物在MDR-MDCK细胞中的渗透性作为血脑屏障渗透性的筛选; 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;和4）合成足够量的两种治疗候选物以支持啮齿动物中的两种可卡因成瘾模型。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，利用科学的力量来解决药物滥用和成瘾问题。我们预计，在这些努力结束时，我们将确定1或2个先导化合物，并验证A2 AR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，并将具有很高的商业和社会价值，对其他成瘾物质如酒精、安非他明和尼古丁具有额外的潜在效用。