Dopamine D2 Receptor Functional Selectivity as a Mechanism of Atypical Antipsychotic Drug Action Public Deposited

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  • March 20, 2019
  • Urban, Jonathan Douglas
    • Affiliation: School of Medicine, Curriculum in Toxicology
  • This project sought to understand how novel receptor mechanisms might play a role in the atypicality of antipsychotic drugs (APDs). The specific focus was on D2 receptor "functional selectivity," the phenomenon by which some ligands selectively activate D2-mediated functional pathways. The first studies examined the effects of a group of chemically diverse atypical antipsychotic drugs on the D2L-mediated activation of MAP kinase phosphorylation and of arachidonic acid release. These studies indicate that only aripiprazole showed partial intrinsic activity at both functional endpoints, whereas all other atypicals were neutral antagonists. Further study of aripiprazole demonstrated unique D2 binding characteristics and no capacity to initiate D2 receptor internalization. Next, site-directed mutagenesis of three transmembrane 5 (TM 5) helix serines (i.e., S5.42A, S5.43A, and S5.46A) was used to study how these residues affected the actions of aripiprazole and other typical partial D2 agonists. These residues play key roles in catecholamine-receptor binding and activity at multiple D2-mediated pathways in CHO cells, and my data illustrate that non-catechols with partial intrinsic activity are uniquely regulated by these serines compared to classical agonists. Finally, a D2L receptor transfected-dopaminergic cell line (N27-D2L) was examined as an in vitro dopaminergic neuronal model. The goal was to use this cell line to study atypical APDs for characterization of their intrinsic activity at D2L-mediated functions (e.g., dopamine uptake and release) at which certain drugs have differential effects in situ. Although these cells initially appeared to be promising dopaminergic models (i.e., they synthesized dopamine, expressed the dopamine transporter, and the transfected D2L receptors coupled to adenylate cyclase), their utility was limited by the fact that dopamine uptake and release, as well as D2L receptor internalization, were not measurable using the methodologies we employed. My data support the hypothesis that at least one major drug (aripiprazole) has unique D2L receptor binding and activating properties that cannot be accommodated by traditional pharmacological theory. In addition, aripiprazole and other functionally selective compounds can be important probes to further our understanding of ligand-receptor interactions, and how this leads to functional changes. This work also suggests reexamination of some current philosophies for rational drug discovery.
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  • Mailman, Richard B.
  • Open access

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