Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor

Fyfe, Tim J.; Kellam, Barrie; Mistry, Shailesh N.; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben

doi:10.1016/j.ejmech.2019.01.061

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor

Fyfe, Tim J.; Kellam, Barrie; Mistry, Shailesh N.; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben

Authors

Tim J. Fyfe

BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry

Dr SHAILESH MISTRY Shailesh.Mistry@nottingham.ac.uk
Associate Professor

Peter J. Scammells

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

Ben Capuano

Abstract

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs (19fc) with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

Citation

Fyfe, T. J., Kellam, B., Mistry, S. N., Scammells, P. J., Lane, J. R., & Capuano, B. (2019). Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor. European Journal of Medicinal Chemistry, 168, 474-490. https://doi.org/10.1016/j.ejmech.2019.01.061

Journal Article Type	Article
Acceptance Date	Jan 24, 2019
Online Publication Date	Feb 11, 2019
Publication Date	Feb 11, 2019
Deposit Date	Feb 12, 2019
Publicly Available Date	Feb 12, 2020
Journal	European Journal of Medicinal Chemistry
Print ISSN	0223-5234
Electronic ISSN	1768-3254
Publisher	Elsevier
Peer Reviewed	Peer Reviewed
Volume	168
Pages	474-490
DOI	https://doi.org/10.1016/j.ejmech.2019.01.061
Keywords	Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
Public URL	https://nottingham-repository.worktribe.com/output/1543596
Publisher URL	https://www.sciencedirect.com/science/article/pii/S0223523419300807?via%3Dihub
Contract Date	Feb 12, 2019