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.
