DOPAMINE AGONISTS FOR THE THERAPY OF COCAINE ADDICTION

多巴胺D_1受体参与可卡因和其他精神运动兴奋剂的强化和其他行为效应的证据表明，D_1机制是开发抗兴奋剂药物的合理靶点。这一药物化学和药理学计划旨在继续开发新的多巴胺D1部分激动剂，具有1)口服生物利用度和较长的作用持续时间，可作为候选治疗药物，2)独特的药理特性(例如，D5与D1的选择性，“非典型”作用模式)作为研究工具。新合成化合物的药理学将在放射性配基结合实验、腺苷环化酶刺激研究以及体内程序中建立，以确定在大鼠和灵长类动物中的效力、作用时间和行为影响。将在可卡因自身给药程序中进一步研究先导化合物，作为抗兴奋剂疗效的临床前测试。这一计划预计会有两个主要结果。首先，一种或多种副作用最小的多巴胺D1部分激动剂将作为治疗精神运动性兴奋剂滥用的候选治疗药物(S)被转发。其次，将开发新的研究工具来研究D1-家族受体亚型和腺苷环化酶在兴奋剂滥用相关和其他行为效应中的中介作用。建议的商业应用：目前，没有统一有效的药物来治疗可卡因滥用和依赖，这仍然是我们最严重的药物滥用问题之一。这种有效药物的开发将对制药业和政府的发展具有重大的商业应用价值。建议合成的化合物都是新颖的和可申请专利的，从而增加了它们的商业价值。

Evidence for dopamine D1 receptor involvement in the reinforcing and other behavioral effects of cocaine and other psychomotor stimulant drugs suggests that D1 mechanisms are rational targets for the development of anti-stimulant medications. This program of medicinal chemistry and pharmacology is intended to continue development of novel dopamine D1 partial agonists with 1) oral bioavailability and long duration of action to advance as candidate therapeutics and 2) unique pharmacological characteristics (e.g., D5 vs. D1 selectivity, 'atypical' profile of action) to serve as research tools. The pharmacology of newly synthesized compounds will be established in radioligand binding experiments, studies of adenylyl cyclase stimulation, and in vivo procedures to determine potency, duration of action, and behavioral effects in rats and primates. Lead compounds will be further studied in cocaine self-administration procedures as a preclinical test of anti-stimulant efficacy. Two major results are expected of this program. First, one or more dopamine D1 partial agonists with minimal side effects will be forwarded as candidate therapeutic(s) for the treatment of psychomotor stimulant abuse. Secondly, new research tools will be developed to study the roles of subtypes of D1- family receptors and of adenylyl cyclase in the mediation of abuse-related and other behavioral effects of stimulant drugs. PROPOSED COMMERCIAL APPLICATION: At present, there are no uniformly effective medications for the treatment of cocaine abuse and dependence, and this remains one of our most serious drug abuse problems. The development of such effective medications would have significant commercial application both for development by the pharmaceutical industry and by the government. The compounds proposed for synthesis are all novel and patentable, thus increasing their commercial value.