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

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

  • Eur J Med Chem. 2019 Apr 15;168:474-490. doi: 10.1016/j.ejmech.2019.01.061.
Tim J Fyfe 1,  Barrie Kellam 2,  Shailesh N Mistry 2,  Peter J Scammells 3,  J Robert Lane 4,  Ben Capuano 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
  • 2 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
  • 3 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
  • 4 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Electronic address: [email protected].
  • 5 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Electronic address: [email protected].
PMID: 30849613 DOI: 10.1016/j.ejmech.2019.01.061
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 with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

Keywords

Agonists; Dopamine D(2) receptor; NAMs; Negative allosteric modulators; Thieno[2,3-d]pyrimidines.

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