Synthesis & Evaluation of Cocaine Antagonists

合成

• 批准号: 6522923
• 负责人: Rae R Matsumoto
• 金额: $ 28.74万
• 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/6522923
• 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）：Coquillo负责更严重的 中毒和死亡比任何其他非法药物，但没有有效的 目前已有可卡因滥用的治疗方法。的一个策略 开发有效的抗可卡因药物是为了阻止可卡因进入其 靶蛋白。在可卡因作用的无数场所中，西格玛 受体是药物开发最有希望的靶点之一。在更早 研究中，我们的团队合成并鉴定了二十多个sigma受体， 拮抗剂，防止可卡因引起的惊厥，致死性， 自发活动有效的化合物都是合成的类似物， 配体BD 1008，和四个系列的化学结构的修改， 在我们以前的研究中对该化合物进行了评价：1）N-烷基 2）吡咯烷基环修饰，3）芳基单取代， （4）构象限制。因此，我们已经确定了具体的 从每个合成系列的修改，最有效地防止 可卡因引起的行为然而，掺入以下物质的组合的化合物 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）开发新的配体， 通过结合我们的最佳结构特征， 早期的具有抗可卡因作用的σ 1拮抗剂，2）证实， 类似于它们的前辈，新化合物具有高亲和力， σ 1受体，但缺乏与非σ位点的相互作用，3）以证实， 新化合物减弱可卡因诱导的行为，但不产生 可能损害其临床潜力的不利副作用，以及4） 来评估结构-活性关系。预计该 该项目的成果将导致新的和有效的发展， 可卡因成瘾和过量的治疗