Significant research findings directed toward specific aims of the current grant were achieved. These accomplishments included: (1) the development of ligands that possessed high affinity and selectivity for the DAT plus chemical and metabolic stability; (2) the development of ligands that possessed high affinity and good selectivity for the serotonin transporter; (3) the identification of three novel structural variations of the cocaine (WIN 35, 065-2) class of compounds as new leads for the development of ligands including new SPECT ligands for studying the DAT; (4) the development and use of [123I] RTI-55 and [123I]RTI-121 as SPECT ligands for studying the DAT in vivo; (5) the development and use of irreversible binding ligands for the dopamine and serotonin transporters. This application is for the continuation of support of the present program. The proposed research continues to be based on the original hypothesis that a structure-activity relationship (SAR) study of cocaine and WIN 35,065-2 analogs designed to provide information about requirements for binding to the cocaine receptor(s) will lead to a better understanding of the basic biochemical mechanism(s) involved in cocaine addiction.
The specific aims are: (1) to prepare larger amounts of some of the compounds prepared in the present application that show high affinity and selectivity for the DAT for further evaluation; (2) to prepare modified analogs of these compounds with the hope of improving their potential as medications for the treatment of cocaine abuse; (3) to design (using SAR, QSAR, and molecular modeling techniques) synthesize, and evaluate compounds for use in further characterizing the cocaine binding site on the dopamine and serotonin transporters; (4) to continue to prepare samples of our irreversibly binding ligands (chemical and photoaffinity) that have been developed for use in the study of the rat brain as well as cloned dopamine and serotonin transporters; and to design and develop new irreversibly binding ligands;(5)to design and synthesize compounds which are new candidate ligands for SPECT and to continue to provide our collaborators as well as others with the precursor needed to prepare [125I]-and [123I] RTI-55 and RTI-l2l, two radioligands that have proven to be useful biochemical probes; (6) to evaluate selected compounds in behavioral assays in animals.
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