The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies indicate that: (1) Many of the known dopamine D2 agonists also have affinity for dopamine D3 receptors. Studies are being conducted in order to discover drugs that are selective for either D2 or D3 receptors. Current studies have focused on the putative D3 receptor agonist PD 128,907. The pharmacology of this compound is being compared to that of other dopaminergic agonists, specifically 7-OH-DPAT and quinpirole. These studies will determine if differences in the in vitro selectivity of these drugs for D2 and D3 dopamine receptors results in behavioral selectivity. In addition, they will provide evidence on the normal physiologic function of the D3 receptor system. (2) Novel dopamine D1 receptor antagonists with a benzazepine nucleus were synthesized. The effects of several N-alkyl substitutions on affinity for dopamine D1 receptors were assessed and the drugs had in vivo and in vitro pharmacology characteristic of D1 antagonists. A terminal amino functionality on the alkyl chain was necessary for optimal binding and selectivity between D1 and D2 dopamine receptors. This terminal amino group conferred the highest affinity when it was between 8 and 9 D from the 3-position benzazepine nitrogen. These results identify a unique binding domain for the D1 dopamine receptor.
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