Synthesis & Evaluation of Cocaine Antagonists

描述(申请人提供)：可卡因引起的中毒和死亡比任何其他非法药物都严重，但没有效果。 目前已有治疗可卡因滥用的方法。其中一个策略是 开发有效的反可卡因药物是为了阻止可卡因进入其 靶蛋白。在可卡因发挥作用的无数场所中，西格玛 受体是药物开发中最有希望的靶点之一。在早些时候 研究表明，我们团队合成并鉴定了20多个西格玛受体 拮抗剂可防止可卡因引起的惊厥、致命性和 活动活动。有效化合物都是合成化合物的类似物。 配体BD1008，以及对其化学结构的四系列修饰 我们在以前的研究中对该化合物进行了评估：1)N-烷基 取代，2)吡咯烷基环修饰，3)芳基单取代， 4)构象限制。因此，我们确定了具体的 来自每个合成系列的最有效的修饰 可卡因诱导的行为。然而，包含以下几种元素组合的化合物 最好的结构特征还有待制造和测试。我们假设 通过结合我们现有化合物的最佳结构特征， 可以获得具有增强的抗可卡因作用的最佳化合物。因此， 该项目的具体目标是：1)开发具有以下特性的新型配体 通过结合我们的最优结构特征来实现药效潜力 早期具有抗可卡因作用的Sigma1拮抗剂，2)证实 与它们的前身类似，新化合物具有很高的亲和力 Sigma1受体，但缺乏与非Sigma位点的相互作用，3)证实 这种新型化合物可以减弱可卡因诱导的行为，但不会产生 可能危及其临床潜力的不良副作用，以及4) 以评估结构-活性关系。据预计， 本项目的成果将导致新的有效的开发 可卡因成瘾和吸毒过量的治疗。

DESCRIPTION (provided by applicant): Cocaine is responsible for more serious intoxications and deaths than any other illicit drug, yet no effective treatments for cocaine abuse are currently available. One strategy for developing effective anti-cocaine agents is to block cocaine's access to its target proteins. Of the myriad of sites through which cocaine can act, sigma receptors are among the most promising targets for drug development. In earlier studies, our group synthesized and identified over two dozen sigma receptor antagonists that prevented cocaine-induced convulsions, lethality, and locomotor activity. The effective compounds are all analogs of the synthetic ligand BD1008, and four series of modifications to the chemical structure of this compound were evaluated in our previous investigations: 1) N-alkyl substitutions, 2) pyrrolidinyl ring modifications, 3) aryl monosubstitutions, and 4) conformational restrictions. As a result, we have identified specific modifications from each synthetic series that are most effective against cocaine-induced behaviors. However, compounds that incorporate combinations of the best structural features have yet to be made and tested. We hypothesize that by combining the best structural features of our existing compounds, optimal compounds with enhanced anticocaine actions can be achieved. Thus, the specific aims of the project are: 1) to develop novel ligands with pharmacophoric potential by combining optimal structural features from our earlier sigma1 antagonists possessing anti-cocaine actions, 2) to confirm that similar to their predecessors, the novel compounds possess high affinity for sigma1 receptors but lack interactions with non-sigma sites, 3) to confirm that the novel compounds attenuate cocaine-induced behaviors, but do not produce unfavorable side effects that could compromise their clinical potential, and 4) to evaluate structure-activity relationships. It is anticipated that the results of this project will lead to the development of new and effective treatments for cocaine addiction and overdose.