Open Collections

Abstract

The two enantiomers of the tetrahydroprotoberberine d,l-govadine synthesized from and studied in the Phillips and Sammis Labs at UBC bring forth distinct outcomes upon interaction with different subtypes of dopamine receptors. With its high binding affinity to D1 receptor, d govadine enhances working memory and behavior flexibility by increasing dopamine efflux in medial prefrontal cortex. l-Govadine, with its high affinity for both D1 and D2 receptors, exhibits properties of atypical antipsychotics as it increases dopamine efflux in both prefrontal cortex and nucleus accumbens. The main purpose of this thesis project is to computationally derive 4 atomic models of the complexes formed by each of the enantiomers with the D1 and D2 receptors to better understand the intermolecular interactions involved in each ligand-receptor pair. The results of the analysis suggested from the distinct binding poses of the two enantiomers may be responsible for d-govadine's ability to improve working memory and behavioral flexibility in contrast to l-govadine's atypical antipsychotic properties. There are notable distinctions in the number and type of polar, non-polar, and aromatic-aromatic intermolecular interactions between the respective ligand-receptor pairs. The detailed analysis of the probable binding models suggests approaches for the rational design of next generation of d-govadine to increase its efficacy as a potential drug for Alzheimer’s Disease, and l-govadine to improve its function as an atypical antipsychotic.