The overall objective of this research is to gain a better understanding of the structural requirements of dopamine agonist (DA) and antagonist activity. The study is centered about the use of a unique non-nitrogen-containing set of DA agonists. Although most investigators have envisioned an uncharged nitrogen as an essential portion of the molecular makeup of agonists and antagonists of DA receptors, we hypothesize that the major role of the nitrogen is to provide a cationic charge on the side chain of the DA molecule, which in turn can bind to an anionic site on the DA receptor. Our initial studies with sulfonium analogs of DA have shown them to possess significant dopamineric activity. In contrast, an uncharged sulfur analog was inactive as a DAergic agonist. We plan to continue these studies with DAergic agonists and to extend these studies to determine the molecular form of DAergic antagonist (charged or uncharged) responsible for antagonist activity. We plan to study the behavioral and biochemical effects of these compounds to determine how these compounds interact with various DA receptor systems (presynaptic, postsynaptic, D1 and D2).
The specific aim of these experiments is to synthesize and characterize several sulfur- and amine-containing agonists and antagonists and determine the molecular form required for agonist and antagonist activity. We will test the effectiveness of the various compounds on several model DAergic receptor systems. These will include 1) the K+ induced release of 3H-acetylcholine from straital slices; 2) circling behavior after the intrastriatal injection of drugs to rats - pretreated with 6-hydroxydopamine; 3) locomotor activity after injection of drugs into the nucleus accumbens of rats; 4) Prolactin release from anterior pituitary cells in culture; 5) inhibition of the binding of radioactive agonist and antagonist drugs. In addition, we will study the effects of the various drugs on the biochemistry of DAergic neurons and on noradrenergic receptor systems.
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