A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D 2 Receptor

Tim J. Fyfe, Barbara Zarzycka, Herman D. Lim, Barrie Kellam, Shailesh N. Mistry, Vsevolod Katrich, Peter J. Scammells, J. Robert Lane*, Ben Capuano

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Recently, a novel negative allosteric modulator (NAM) of the D 2 -like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

Original languageEnglish
Pages (from-to)174-206
Number of pages33
JournalJournal of Medicinal Chemistry
Volume62
Issue number1
DOIs
Publication statusPublished - 1 Oct 2019
Externally publishedYes

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