DESCRIPTION: (Applicant's Abstract) Dr. F. Ivy Carroll of the Research Triangle institute (RTI) has established a collaboration with Dr. James L. Howard of Howard Associates and Dr. George F. Koob of the Scripps Research Institute to conduct animal behavioral studies on compounds synthesized at RTI.  The initial compounds selected for study are based on inhibition of radioligand binding data at the dopamine transporter (DAT) and reuptake of dopamine (DA) relative to similar data for the serotonin (5-HT) and norepinephrine (NE) systems, and some preliminary animal behavioral data from the CTDP, the Medical College of Virginia, Wake Forest University, and our own laboratory.  As behavioral data accumulate, the structure-activity relationship (SAR) developed will guide compound selection from the existing library and the synthesis of additional compounds.  Over the past several years, our laboratory conducted an SAR study to characterize the cocaine binding site on the DAT and 5-HTT with the hope of gaining information on cocaine's biochemical mechanism of action.  The study has involved the synthesis and in vitro evaluation of over 400 cocaine and WIN 35,065-2 analogs.  Results on the WIN 35,065-2 class are particularly interesting because compounds were discovered which showed (1) high affinity for the DAT but very low affinity for the 5-HTT and NET, (2) high affinity for the 5-HTT but very low affinity for the DAT and NET.  and (3) high affinity for the DAT and 5-HTT but low affinity for the NET.  The specific aim of this application is to synthesize and conduct animal behavioral studies on thirty (30) WIN 35,065-2 analogs per year.  The animal studies will be (1) observation in mouse, (2) locomotor activity in mouse, (3) drug discrimination in rat, and (4) self-administration in rat.  In addition, oral activity, broad pharmacology, and subchronic administration will be assessed for selected analogs.  Because all compounds are derived from one structural class of monoamine uptake inhibitors, animal behavioral effects due to other factors will be lessened.  The major goal of the proposed research is to discover candidate compounds for evaluation as treatment for cocaine abuse.  The central hypothesis of this research is that a compound which is "cocaine-like" but which has a slow onset of action and an extended duration of action would be a useful therapeutic agent.  An ideal candidate compound would not only have efficacy in the preclinical models but would be safe, orally active, and potent, would not show tolerance or sensitization, and if abusable, would be less so than cocaine.