NOVEL PHARMACOTHERAPY FOR TREATMENT OF COCAINE ADDICTION

本申请是对SPIRCAP RFA DA 00-001的回应。该应用程序汇集了来自六个不同组织的经验丰富的调查人员，他们对开发治疗可卡因成瘾的药物感兴趣。F博士三角研究所的艾薇卡罗尔、芭芭拉S。福克斯从成瘾治疗，詹姆斯L。霍华德联合公司的霍华德，伦纳德博士。埃默里大学的豪厄尔博士、查尔斯·R.来自韦恩州立大学的Schuster和Chris Ellyn Johanson博士，以及托马斯R.和特蕾莎·A.来自耶鲁大学的Korsten这些研究者在有机和药物化学、动物行为药理学和临床评价方面具有丰富的经验。尽管已经为解决可卡因成瘾问题付出了相当大的努力，但目前还没有合适的药物治疗。作为NIDA支持的其他项目的一部分，我们已经发现了新的3-苯基托烷类似物，这些类似物具有的性质提供了这些化合物之一将用作治疗可卡因成瘾者而没有有害副作用的药物的希望。已经发现并开发了显示高亲和力的新型3-苯基托烷类似物。动物行为研究表明，这些化合物中的一些具有治疗药物所需的药理学性质。为了利用这一重大发展，本申请提出了首先在人体中进行临床前研究，然后进行临床研究的建议，以确定DAT选择性3-苯基托烷类似物作为治疗可卡因成瘾者的药物的潜力。待检验的假设是：（1）对DAT具有高度选择性的3-苯基托烷类似物可安全地用于人类;（2）DAT选择性3-苯基托烷可用于治疗对可卡因成瘾的人类;和（3）可卡因选择性再摄取抑制剂如氟西汀、帕罗西汀和舍曲林将调节由DAT选择性3-苯基托烷诱导的行为效应。

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.