The primary objective of this competitive revision to R01 DA12970 is to assess compounds in a variety of functional endpoints of the 5HT1a, 5HT2a, 5HT2b and 5HT2c receptors. The goals are two-fold, (1) to speed up the discovery and development of safe medications for the treatment of substance abuse by eliminating all 5HT1a, 5HT2a, and 5HT2b activity from the releasers developed on the parent grant;and (2) to identify functionally selective compounds of these receptors to use as tools for determining which second messenger pathways are connected to specific behavioral or efficacy endpoints. The initial objective of the parent grant program is to design, synthesize, and evaluate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) releasers. To date, most efforts towards an "agonist" therapy of stimulant addiction have concentrated on the discovery of selective DA uptake blockers. However increasing evidence shows that dual DA/5-HT selective or non-selective compounds may be required to "correct" the totality of stimulant-induced deficits during withdrawal. A project aim in the competitive revision is to screen compounds at 5HT1a, 5HT2a, and 5HT2b receptors to eliminate activity for safety reasons. 5HT1a and 5HT2a agonist activity has been linked to hallucinogenic activity. 5HT2b has been linked to pulmonary valvulopathy. The parent grant contains screening of these receptors, but only using receptor-induced calcium mobilization as the indicator of agonist activity. Emerging evidence suggests that calcium efflux does not completely correlate in either case, and that a wider array of functional endpoints is required to ensure elimination of this activity. Compounds will be assessed at 5 additional endpoints for each of the three receptors. Elimination of activity will ensure the development of safer drug candidates. In the process functionally selective agonists for each receptor will also be identified as tools for the study of functionally selective ligands. The 5HT2c receptor will also be included since recent evidence shows that 5HT2c agonist activity may be useful in a stimulant-addiction medication, especially in relapse. PUBLIC HEALTH RELEVANCE: Stimulant abuse and addiction continues to be a major societal problem the United States. Mounting evidence suggests that one of the best methods for combating stimulant addiction is the agonist approach in which drugs replace the biochemical deficits caused by chronic stimulant. Such an approach may be the only way to address the wide ranges of symptoms observed during withdrawal as well as the urge to relapse into drug taking behavior. Safe, dual dopamine/serotonin releasers represent one approach to such agonist therapies and will be developed in this research program.