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Reason: Under embargo until Aug 2017. After this date a copy can be supplied under Section 51(2) of the Australian Copyright Act 1968 by submitting a document delivery request through your library
Investigations of adenosine A2A receptor antagonists, dopamine D2 receptor agonists and dual acting ligands for the treatment of parkinson’s disease
thesisposted on 2017-01-23, 21:45 authored by Jorg, Manuela
In this project, the adenosine A2A receptor and the dopamine D2 receptor were studied as potential targets for the treatment of Parkinson’s disease. Investigated were both targets individually as well as the approach to target both receptors simultaneously with just one single molecule. Herein, present is the synthesis, characterization and pharmacological evaluation of the literature compound ZM 241385 and a series of structurally related adenosine A2A receptor antagonists. Further determined was a chemically and biologically suitable attachment position for linkers on the parent pharmacophores. From this research a triazolotriazine carboxylic acid congener with inhibitory potency equivalent to ZM 241385 has been established, allowing further functionalization towards the extracellular space of the adenosine A2A receptor. At the dopamine D2 receptor, a chemically and biologically suitable attachment position on the chemical structure of the dopamine D2 receptor agonist ropinirole was determined, allowing the development of an oxindole carboxylic acid and an oxindole amine congener. Based on these results a series of homobivalent ligands was synthesized, characterized and pharmacologically evaluated. The homobivalent ligands with a spacer length of 22 to 30 atoms exhibited up to an 80-fold increase in potency compared to the parent molecule ropinirole. Docking of the synthesized molecules in a dopamine D2 receptor dimer model indicated that the increase in potency of the homobivalent ligands was most likely due to an additional allosteric interaction and very unlikely due to interactions at two orthosteric sites across a homodimer. The research results from targeting each receptor individually formed the pillars for the synthesis, characterization and pharmacological evaluation of our dual acting ligands targeting the dopamine D2 and adenosine A2A receptors with just one molecule. A library of compounds ranging from classical heterobivalent ligands to more drug-like merged molecules was synthesized. The most encouraging higher integrated “drug-like” molecules exhibited promising initial blood-brain barrier permeability results and maintained similar EC50 values to the dopamine D2 receptor agonist ropinirole but showed a slight decrease in inhibitory potency compared to the adenosine A2A receptor antagonist ZM 241385. Conversely, the pharmacological evaluation of the dual acting ligands revealed that the most potent classical heterobivalent ligands showed comparable affinities to both original pharmacophores.