Dopamine D1 Like Receptors

Author : Emily Frieben
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (13 download)

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Download or read book Dopamine D1-like Receptors written by Emily Frieben and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The dopamine D1-like receptors (D1 and D5) are implicated in the etiology of both neurological and non-neurological conditions. For decades, the therapeutic utility of dopamine D1 receptor (D1R) agonists has been exemplified by their efficacy in animal models of Parkinson's disease (PD) and in PD patients. Despite showing promise, no centrally-available D1-like agonists have been approved, being hindered by poor pharmacokinetics and side effects. Recent advances have allowed for several non-catechol D1 agonists to advance to clinical trials for early- and late-stage PD. These compounds are functionally selective, with high bias for G protein over [beta]-arrestin signaling. There is limited knowledge, however, regarding how ligands precisely bind and activate the D1-like receptors. To guide structure-based drug design, we developed an experimentally-validated homology model of the D1 receptor that could offer understanding of how differences in ligand structure could lead to activation of specific signaling pathways. We studied molecular interactions of the D1R with three conformationally-constrained ligands [the prototypical full D1R agonist dihydrexidine (DHX), and monohydroxy analogs ("10-OH DHX", "11-OH DHX")], and compared them to dopamine and SKF38393. We focused on three critical serines in transmembrane V (TM5), residues S5.42 (S198), S5.43 (S199), and S5.46 (S202), which were mutated to alanine singly or in combination and then characterized. Docking simulations identified S5.42 and S5.46 as potentially important interactions. Binding assays were impossible with the S5.42A mutant, but functional assays revealed that the S5.42A receptor had activity when the ligand contained a 10-hydroxyl group, and none with only the 11-hydroxyl. The 11-hydroxyl position of DHX interacted with S5.42 and S5.43, whereas the 10-hydroxyl interacted with S5.46. These stereochemical preferences were apparent across the mono-hydroxy analogs. We then employed our structural model of the D1R to predict interactions for several non-catechol agonists, including the clinical candidate tavapadon/CVL-751. We identified the S5.46 interaction as a key determinant for agonist activity. Taken together, this data provides valuable insight into structural features that govern binding and activation of the D1R, which may aid in the design of clinically relevant D1 agonists. In the last decade, the D1-like receptors have been recognized for their utility in a number of non-neurological conditions. With the wide plethora of drugs and experimental compounds that target these receptors, many studies have evaluated their potential for repurposing. Of interest is the notion that the D1-like dopamine receptors, most recently the D5 receptor (D5R), may be implicated in the etiology of and/or may serve as a therapeutic target in various cancers. This idea stemmed from pharmacoepidemiological studies suggesting a lower cancer risk in patients with schizophrenia or PD, reported up-regulations of the dopamine receptors in various cancers, dopaminergic regulation of tumor behavior, and extensive research with D2 receptor antagonists in cancer. Although this seems exciting, critical analysis of the growing D5R cancer literature was instead quite illustrating. There were flawed hypotheses, experimental design without consideration of pharmacological principles, a dearth of rigorous controls, and improper applications of statistics. It is very likely that the reported "anticancer" effects actually were false positives and conclusions made erroneously. This body of confounded data suggests that there is little therapeutic value for the D5R in cancer and that more rigorous studies are warranted. The lack of rigor issue is a widespread problem and applicable across all disciplines in the biomedical sciences. Therefore, to shed light on this growing problem, we reviewed these recent studies with the D5R and put them in a broader context, with emphasis on the pharmacological fundamentals. The findings of this analysis are meant to educate and remind the greater scientific community that adherence to established biological principles must be as rigorous as the proper application of statistics. En masse, this dissertation provides understanding into the relationship between ligand structure and D1R function, as well as insight into the role of the D5R in cancer therapeutics. These data lay the foundation for more studies to investigate further the molecular interactions governing binding and activation of the D1-like receptors, which can be used to guide the design of functionally selective and/or subtype-selective ligands. Together, the findings presented herein not only affect the design of future studies, but also the interpretation of previous literature on D1-like receptor structure and function.