A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor

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

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, whilst 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.

Citation

Fyfe, T. J., Zarzycka, B., Lim, H. D., Kellam, B., Mistry, S. N., Katrich, V., …Capuano, B. (2019). A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor. Journal of Medicinal Chemistry, 62(1), 174–206. https://doi.org/10.1021/acs.jmedchem.7b01565

• Journal Article Type: Article
• Acceptance Date: Apr 23, 2018
• Online Publication Date: Apr 23, 2018
• Publication Date: Jan 10, 2019
• Deposit Date: Apr 24, 2018
• Publicly Available Date: Apr 24, 2019
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 62
• Issue: 1
• Pages: 174–206
• DOI: https://doi.org/10.1021/acs.jmedchem.7b01565
• Public URL: https://nottingham-repository.worktribe.com/output/927590
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01565
• Additional Information: This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01565.