DOPAMINE AGONISTS FOR THE THERAPY OF COCAINE ADDICTION

描述（改编自应用程序）：药物化学程序 和药理学提出了新的多巴胺的合成和评价 D1受体配体治疗可卡因成瘾和其他精神疾病 滥用兴奋剂。这项提议的动力来自初步的 临床前研究结果显示，D1部分激动剂SKF 83959 a 1-芳基-3-苯并氮杂卓可能减少可卡因的滥用相关作用， 副作用责任。本申请人提出合成新型衍生物， 外消旋SKF 83959，可能具有更高的效力和更长的持续时间， 行动上这些将包括SKF 83959的对映体;具有受保护的 邻苯二酚部分上的羟基官能团，以及卤代或烷基化的 衍生物.新合成配体的药理学将建立 用：1）体外方法测定多巴胺D1受体选择性， 放射性配体结合实验和2）测定效价的体内程序 和作用持续时间，并进一步评估激动剂 在眨眼行为测定和木僵诱导的逆转中的有效性 多巴胺D1受体阻滞剂，这项研究预计将导致一个或 更多的多巴胺D1部分激动剂，作用持续时间延长， 副作用作为候选抗可卡因药物的进一步开发。 拟定商业应用： 目前，对于可卡因的治疗还没有统一有效的药物 这仍然是我们最严重的毒品问题之一。的 开发这种有效的药物将具有重要的商业价值。 应用于制药行业和政府的开发。

DESCRIPTION (Adapted from the application): A program of medicinal chemistry and pharmacology is proposed for the synthesis and evaluation of novel dopamine D1 receptor ligands to treat addiction to cocaine and other psychomotor stimulant drugs of abuse. The impetus for this proposal comes from preliminary findings in preclinical studies showing that the D1 partial agonist SKF 83959 a 1- aryl-3-benzazepine may decrease abuse-related effects of cocaine with little side-effect liability. The applicant proposes to synthesize novel derivatives of racemic SKF 83959 that may have increased potency and longer duration of action. These will include enantiomers of SKF 83959; cogeners with protected hydroxy functions on the catechol moiety, and halogenated or alkylated derivatives. The pharmacology of newly synthesized ligands will be established with: 1) in vitro procedures to determine dopamine D1 receptor selectivity in radioligand binding experiments and 2) in vivo procedures to determine potency and duration of action in a primate species and to further evaluate agonist efficacy in behavioral assays of eyeblinking and reversal of catalepsy induced by dopamine D1 receptor blockade, This research is expected to result in one or more dopamine D1 partial agonists with increased duration of action and minimal side effects for further development as candidate anti-cocaine medications. 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 problems. The development of such effective medications would have significant commercial application both for development by the pharmaceutical industry and by the government.