Structural basis for ligand-binding and activation of D1-like dopamine receptors Public Deposited

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  • March 22, 2019
Creator
  • Brown, Justin T.
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • The D1-like dopamine receptors have been implicated in the etiology of several neurological and psychiatric disorders. Recent advances in neurobiology have demonstrated the potential utility of D1-like dopamine receptor agonists as therapeutic compounds. Despite immense promise, there are no D1 centrally available agonists currently available as therapeutic compounds. Moreover, there are no selective ligands that can distinguish between the two D1-like receptors (D1 and D5). One of the major obstacles to the discovery of such agents is limited information about the structural basis for ligand-binding and activation of the D1-like receptors. There are few such studies that have been done with the D1 receptor, and virtually none with the D5 receptor. This dissertation was aimed at gaining a greater understanding of the structural mechanisms necessary for ligand-binding, receptor activation, and receptor internalization. Rationally- selected point mutations of the D1-like receptors were made, and detailed analysis of binding and function made for a series of structurally and functionally diverse test compounds. Work in this dissertation provides the first experimental evidence that T3.37 plays an important role in binding and activation of D1-like receptors. Studies of a TM6 phenylalanine at residue at position 6.51 revealed that this residue plays a key role in coupling ligand binding to receptor activation. Studies of another aromatic residue
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology.
Advisor
  • Mailman, Richard B.
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