The objective of the proposal is to evaluate a novel therapeutical approach in the treatment of cocaine abuse, based on the use of selective partial dopamine D3 receptor (D3R) agonists. Psychostimulants like cocaine unconditionally evoke dopamine release in the shell of nucleus accumbens, in which the D3R is rather selectively expressed. Moreover, dopamine agonists decrease cocaine self-administration in rats, with a potency highly related to their in vitro D3R, but not D2R, potency, suggesting that the D3R participates in the reinforcing effects of cocaine. Accordingly, partial D3R agonists would normalize dopamine transmission upon cocaine withdrawal, at which dopamine levels are lowered, and thereby partially substitute for cocaine and disrupt cocaine seeking, with minimal liability of dependence to these agents. Novel D3R ligands, namely partial agonists, with increased selectivity, brain bioavailability and duration of action will be synthesized (~100 molecules during the program). Molecular modeling and structure-activity relationship studies will be performed with already identified compounds among substituted naphtamides, having marked D3R over D2R selectivity and intrinsic activity ranging from 0 (antagonist) to 0.60 (partial agonist). The D3R potency and selectivity, namely as regards to the D2R, of new compounds will be assessed on recombinant human receptors expressed by transfected cells by measuring their binding affinity and intrinsic activity. The functional tests are based on mitogenesis and inhibition of cAMP formation. The bioavailability (p.o.), D3R occupancy and in vivo potency of selected compounds will be assessed in rodents using D3R radioreceptor assay and quantitative in situ hybridization of brain mRNAs. These functional tests will allow the determination of the in vivo potency and intrinsic activity of the compounds. The most promising compounds will be then tested in four behavioral procedures, initially full agonists, partial agonists to full antagonists, in order to determine the optimal intrinsic activity for maximal potential therapeutic efficacy. The efficacy of D3R agonists to reduce or disrupt cocaine self-administration will be measured in monkeys, and compared to their efficacy for suppressing food-maintained responding. The liability to dependence to D3R agonists will be evaluated in drug discrimination and substitution models in mice. The whole stepwise process will take place with the aim of a quick transfer to clinical appraisal of one candidate.
