Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor

Monika Szabo, Carmen Klein Herenbrink, Arthur Christopoulos, Jonathan Robert David Lane, Benvenuto Capuano

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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.
Original languageEnglish
Pages (from-to)4924 - 4939
Number of pages16
JournalJournal of Medicinal Chemistry
Volume57
Issue number11
DOIs
Publication statusPublished - 2014

Cite this

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title = "Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor",
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.",
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Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor. / Szabo, Monika; Klein Herenbrink, Carmen; Christopoulos, Arthur; Lane, Jonathan Robert David; Capuano, Benvenuto.

In: Journal of Medicinal Chemistry, Vol. 57, No. 11, 2014, p. 4924 - 4939.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor

AU - Szabo, Monika

AU - Klein Herenbrink, Carmen

AU - Christopoulos, Arthur

AU - Lane, Jonathan Robert David

AU - Capuano, Benvenuto

PY - 2014

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AB - 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.

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