NOVEL PHARMACOTHERAPY FOR TREATMENT OF COCAINE ADDICTION

本申请是对SPIRCAP RFA DA 00-001的响应。该申请汇集了一组经验丰富的调查员，他们来自六个不同的组织，对开发治疗可卡因成瘾的药物感兴趣。三角研究所的F. Ivy Carroll博士，成瘾疗法的Barbara S. Fox博士，霍华德联合公司的James L. Howard博士，埃默里大学的Leonard L. Howell博士，韦恩州立大学的Charles R. Schuster和Chris Ellyn Johanson博士。来自耶鲁大学的Thomas R.和Theresa A. Korsten。这些研究人员在有机化学和药物化学、动物行为药理学和临床评估方面拥有丰富的经验。尽管在解决可卡因成瘾问题上已经付出了相当大的努力，但目前还没有合适的药物治疗方法。作为NIDA支持的其他项目的一部分，我们已经发现了新的3-苯tropane类似物，它具有的特性提供了希望，其中一种化合物将作为治疗可卡因成瘾者的有效药物，而不会产生有害的副作用。新的具有高亲和力的3-苯基tropane类似物被发现和开发。动物行为学研究表明，其中一些化合物具有治疗药物所需的药理特性。为了利用这一重大发展，本申请提出了一项建议，首先进行临床前研究，然后在人体中进行临床研究，以确定DAT选择性3-苯tropane类似物作为治疗可卡因成瘾者的药物的潜力。需要验证的假设是：(1)对DAT具有高度选择性的3-苯基tropane类似物将安全用于人类；(2)一种具有dat选择性的3-苯tropane可用于治疗可卡因成瘾者；(3)氟西汀、帕罗西汀和舍曲林等5 -羟色胺选择性再摄取抑制剂可调节dat选择性3-苯tropane诱导的行为效应。

This application is in response to SPIRCAP RFA DA 00-001. The application brings together a group of experienced investigators from six separate organization who have an interest in developing medications for the treatment of cocaine addiction. Dr. F. Ivy Carroll from the Research Triangle Institute, Dr. Barbara S. Fox from Addiction Therapies, Dr. James L. Howard from Howard Associates, Dr. Leonard L. Howell from Emory University, Drs. Charles R. Schuster and Chris Ellyn Johanson from Wayne State University, and Drs. Thomas R. and Theresa A. Korsten from Yale University. These investigators have extensive experience in organic and medicinal chemistry, animal behavioral pharmacology, and clinical evaluation. Even though considerable effort has been devoted toward solving the cocaine addiction problem, no suitable pharmacotherapy is presently available. As part of other programs supported by NIDA, we have discovered novel 3-phenyltropane analogs which possess properties that provide promise that one of these compounds will be useful as a medication for treating cocaine addicts without deleterious side effects. Novel 3-phenyltropane analogs that show high affinity have been discovered and developed. Animal behavioral studies have shown that some of these compounds possess pharmacological properties desirable for a treatment medication. In order to take advantage of this significant development, the present application puts forth a proposal to first conduct preclinical and then clinical studies in humans to determine the potential of the DAT selective 3- phenyltropane analogs as medications for treatment of cocaine addicts. The hypotheses to be tested are: (1) a 3-phenyltropane analog highly selective for the DAT will be safe to use in humans; (2) a DAT-selective 3-phenyltropane will be useful for treating humans addicted to cocaine; and (3) serotonin-selective reuptake inhibitors such as fluoxetine, paroxetine, and sertraline will modulate the behavioral effects induced by the DAT-selective 3-phenyltropane.