Synthesis & Evaluation of Cocaine Antagonists

合成

• 批准号: 6435744
• 负责人: Rae R Matsumoto
• 金额: $ 28.93万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6435744
• 关键词: PCP receptor; behavior test; body physical activity; cocaine; drug addiction antagonist; drug design /synthesis /production; drug receptors; drug screening /evaluation; laboratory mouse; receptor binding

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.

描述（由申请人提供）：可卡因比任何其他非法药物造成更严重的中毒和死亡，但尚无有效的方法 目前可以治疗可卡因滥用。一项策略 开发有效的抗可卡因药物就是阻止可卡因进入其体内 目标蛋白质。在可卡因发挥作用的无数位点中，西格玛 受体是药物开发最有希望的靶标之一。在早些时候 研究中，我们的小组合成并鉴定了超过两打西格玛受体 拮抗剂可预防可卡因引起的惊厥、致死率和 运动活动。有效的化合物都是合成化合物的类似物 配体BD1008，并对化学结构进行了四个系列的修饰 该化合物在我们之前的研究中进行了评估：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。结果，我们确定了具体的 每个合成系列的修改最有效 可卡因诱发的行为。然而，包含以下组合的化合物 最佳的结构特征还有待制作和测试。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）开发新型配体 通过结合我们的最佳结构特征来发挥药效潜力 早期的 sigma1 拮抗剂具有抗可卡因作用，2) 证实 与它们的前身相似，这些新型化合物对 sigma1 受体，但缺乏与非 sigma 位点的相互作用，3) 确认 这些新型化合物可以减弱可卡因引起的行为，但不会产生 可能损害其临床潜力的不利副作用，以及 4) 评估结构-活性关系。预计 该项目的成果将导致开发新的、有效的 可卡因成瘾和过量的治疗。