The positive reinforcing effects of cocaine have proven to be an important determinant of its abuse liability. Neurochemical studies have linked cocaine's reinforcing effects with the inhibition of dopamine uptake, and microdialysis studies have shown that cocaine causes a rapid and transient increase in synaptic dopamine levels in the limbic dopaminergic system. Recent advances in molecular biology have revealed the existence of additional subtypes of dopamine receptors, the D3, D4, and D5 receptors, which are located exclusively in limbic regions of brain. Behavioral studies have shown that Dl, D2, and D3 receptors are involved in the reinforcing effects of cocaine since selective antagonists for these receptors can block cocaine self-administration in primates. However, use of D2 antagonists to treat cocaine abuse has yielded discouraging results due to the occurence of unwanted extra-pyramidal side-effects. These side-effects have also been well-documented in the treatment of schizophrenia with D2 antagonists. It has been suggested that newer agents displaying a higher affinity for D3 vs D2 receptors should have a higher therapeutic efficacy in treating schizophrenia, and a similar argument can be made for treating cocaine abuse. As part of a research program aimed at developing radioligands that can be used with the in vivo imaging technique Positron Emission Tomography, we identified a class of compounds having a high affinity for both D2 and D3 receptors. We recently discovered that these agents are also very potent in blocking cocaine self-administration in rhesus monkeys. However, at high doses of drug tested, significant extrapyramidal side-effects were observed. The goal of the research described in this proposal is to conduct a series of structure-activity relationship studies as a means of preparing newer analogues having a higher D3:D2 (and/or D4:D2) selectivity in order to eliminate the extra-pyramidal side effects of these compounds while maintaining their cocaine antagonist properties. The affinity of all new analogues for D2, D3, and D4 receptors will be tested as part of a companion application entitled """"""""Pharmacotherapy of Cocaine Abuse. 2. Pharmacology,"""""""" R.R. Luedtke, P.I. Promising compounds will be tested as part of the research described in the application entitled """"""""Pharmacotherapy of Cocaine Abuse. 3. Behavioral Studies,"""""""" M.A. Nader, P.I. Radiolabeled and irreversibly-binding analogues of compounds displaying a high selectivity for D2, D3, or D4 receptors will be prepared as a means of studying the molecular pharmacology of these receptors. These analogues will be of value in mapping-out the pharmacophore of the D2, D3, and D4 receptors.
