SYNTHESIS & EVALUATION OF D3R LIGANDS FOR COCAINE ABUSE

描述：（申请人摘要） 该提案的目的是评估一种新的治疗方法 在可卡因滥用治疗中，基于使用选择性局部 多巴胺D3受体（D3 R）激动剂。 可卡因之类的精神兴奋剂 无条件地引起多巴胺释放在壳的核， 其中D3 R是选择性表达的。 此外，多巴胺激动剂 减少大鼠的可卡因自我给药，与效力高度相关 其体外D3 R，而不是D2 R，效力，表明D3 R 参与可卡因的强化作用。 因此，部分 D3 R激动剂将使可卡因戒断时的多巴胺传递正常化， 多巴胺水平降低，从而部分替代 可卡因和破坏可卡因寻求，以最小的依赖性， 这些代理人。 具有增加的选择性的新型D3 R配体，即部分激动剂， 将合成脑生物利用度和作用持续时间（~100 程序中的分子）。 分子模拟与构效关系 将使用已鉴定的化合物进行关系研究 在取代的萘酰胺中，具有显著的D3 R相对于D2 R的选择性， 内在活性范围为0（拮抗剂）至0.60（部分激动剂）。 新化合物的D3 R效力和选择性，即关于D2 R， 化合物将在重组人受体上进行评估， 通过测量它们的结合亲和力和内在的 活动 功能测试是基于有丝分裂和抑制 cAMP形成。 生物利用度（p.o.），D3 R占用率和体内 将使用D3 R在啮齿动物中评估所选化合物的效力 放射受体测定和定量原位杂交的脑mRNA。 这些功能试验将允许测定体内效价 和化合物的内在活性。 最有希望的化合物将在四个行为测试中进行测试。 程序，最初完全激动剂，部分激动剂到完全拮抗剂， 为了确定最大潜力的最佳内在活性， 疗效 D3 R激动剂降低或破坏 将在猴子中测量可卡因自我给药，并与 它们抑制食物维持反应的功效。 的法律责任 将在药物辨别中评价对D3 R激动剂的依赖性， 小鼠的替代模型。 整个过程将逐步进行 目的是快速转移到一个候选人的临床评估。

DESCRIPTION: (Applicant's Abstract) The objective of the proposal is to evaluate a novel therapeutical approach in the treatment of cocaine abuse, based on the use of selective partial dopamine D3 receptor (D3R) agonists. Psychostimulants like cocaine unconditionally evoke dopamine release in the shell of nucleus accumbens, in which the D3R is rather selectively expressed. Moreover, dopamine agonists decrease cocaine self-administration in rats, with a potency highly related to their in vitro D3R, but not D2R, potency, suggesting that the D3R participates in the reinforcing effects of cocaine. Accordingly, partial D3R agonists would normalize dopamine transmission upon cocaine withdrawal, at which dopamine levels are lowered, and thereby partially substitute for cocaine and disrupt cocaine seeking, with minimal liability of dependence to these agents. Novel D3R ligands, namely partial agonists, with increased selectivity, brain bioavailability and duration of action will be synthesized (~100 molecules during the program). Molecular modeling and structure-activity relationship studies will be performed with already identified compounds among substituted naphtamides, having marked D3R over D2R selectivity and intrinsic activity ranging from 0 (antagonist) to 0.60 (partial agonist). The D3R potency and selectivity, namely as regards to the D2R, of new compounds will be assessed on recombinant human receptors expressed by transfected cells by measuring their binding affinity and intrinsic activity. The functional tests are based on mitogenesis and inhibition of cAMP formation. The bioavailability (p.o.), D3R occupancy and in vivo potency of selected compounds will be assessed in rodents using D3R radioreceptor assay and quantitative in situ hybridization of brain mRNAs. These functional tests will allow the determination of the in vivo potency and intrinsic activity of the compounds. The most promising compounds will be then tested in four behavioral procedures, initially full agonists, partial agonists to full antagonists, in order to determine the optimal intrinsic activity for maximal potential therapeutic efficacy. The efficacy of D3R agonists to reduce or disrupt cocaine self-administration will be measured in monkeys, and compared to their efficacy for suppressing food-maintained responding. The liability to dependence to D3R agonists will be evaluated in drug discrimination and substitution models in mice. The whole stepwise process will take place with the aim of a quick transfer to clinical appraisal of one candidate.