Skip to main content

Research Repository

Advanced Search

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

Profile Image

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

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

Files




You might also like



Downloadable Citations