ArticleBioorganic & medicinal chemistry letters2021
Development of pyrimidone D1 dopamine receptor positive allosteric modulators.
Article in Bioorganic & medicinal chemistry letters, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Elucidating biased signaling in class A GPCRs.Trends in pharmacological sciences · 2025Review
- The Molecular Mechanism of Positive Allosteric Modulation at the Dopamine D1 Receptor.International journal of molecular sciences · 2023Article
- The molecular mechanism of positive allosteric modulation at the dopamine D1 receptor.bioRxiv : the preprint server for biology · 2023Article
- Loss-of-Function Variants inCells · 2023Article
- Ligand recognition and biased agonism of the D1 dopamine receptor.Nature communications · 2022Article
- The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs.Frontiers in pharmacology · 2022Review
- Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine DMolecules (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure-activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators.
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Registered trials
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