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。 在治疗可卡因滥用的基础上，使用选择性局部 多巴胺D3受体(D3R)激动剂。像可卡因这样的精神刺激剂 无条件地引起伏隔核壳内多巴胺的释放 其中D3R是相当有选择性地表达的。此外，多巴胺激动剂 减少大鼠对可卡因的自我给药，与其效力高度相关 对它们的体外D3R，但不是D2R的效力，这表明D3R 参与可卡因的强化作用。相应地，部分 D3R激动剂会在可卡因戒断后使多巴胺传递正常化， 降低多巴胺水平，从而部分取代 可卡因和扰乱可卡因寻找，依赖的责任最小 这些特工。 新型D3R配体，即部分激动剂，具有更高的选择性， 将综合大脑生物利用度和作用持续时间(~100 计划期间的分子)。分子模拟与构效关系 将对已确定的化合物进行关系研究 在取代的萘胺中，标记为D3R而不是D2R选择性和 内源活性从0(拮抗剂)到0.60(部分激动剂)。 D3R的效力和选择性，即关于D2R，新的 化合物将在重组人受体上进行评估，表达方式为 通过测量其结合亲和力和内源性来检测转基因细胞 活动。功能测试是基于有丝分裂和抑制细胞分裂。 阵营队形。生物利用度(P.O.)、D3R占有率和体内 所选化合物的效力将使用D3R在啮齿动物身上进行评估 脑mRNAs的放射受体分析和定量原位杂交。 这些功能测试将允许确定体内的效力 和化合物的内在活性。 然后，最有希望的化合物将在四种行为中进行测试 程序，最初的完全激动剂，部分激动剂到完全拮抗剂， 为了确定最大势能的最佳本征活度 治疗效果。D3R激动剂减少或干扰D3R的疗效 可卡因的自我给药将在猴子身上进行测量，并与 它们抑制食物维持的反应的功效。对……的责任 对D3R激动剂的依赖将在药物歧视和 小鼠的代用模型。整个循序渐进的过程将会发生 目的是快速转移到一名候选人的临床评估。

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.