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

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
• Acceptance Date: Mar 24, 2014
• Online Publication Date: May 30, 2014
• Publication Date: Jun 12, 2014
• Deposit Date: Apr 22, 2020
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 57
• Issue: 11
• Pages: 4924-4939
• DOI: https://doi.org/10.1021/jm500457x
• Public URL: http://pubs.acs.org/doi/abs/10.1021/jm500457x
• Publisher URL: https://pubs.acs.org/doi/abs/10.1021/jm500457x