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Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D 2Receptor

Szabo, Monika; Klein Herenbrink, Carmen; Christopoulos, Arthur; Lane, J Robert; Capuano, Ben

Authors

Monika Szabo

Carmen Klein Herenbrink

Arthur Christopoulos

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

Ben Capuano



Abstract

Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.

Journal Article Type Article
Publication Date Jun 12, 2014
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 57
Issue 11
Pages 4924-4939
APA6 Citation Szabo, M., Klein Herenbrink, C., Christopoulos, A., Lane, J. R., & Capuano, B. (2014). Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D 2Receptor. Journal of Medicinal Chemistry, 57(11), 4924-4939. https://doi.org/10.1021/jm500457x
DOI https://doi.org/10.1021/jm500457x
Publisher URL https://pubs.acs.org/doi/abs/10.1021/jm500457x
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