ArticleBiochemical pharmacology2021
Discovery of small molecule positive allosteric modulators of the secretin receptor.
Article in Biochemical pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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The trial behind it
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Identification and Characterization of a Phenyl(trifluoro-methyl)-pyrimidine Positive Allosteric Modulator of the Secretin Receptor.Membranes · 2026Article
- Structure-activity relationships of thiadiazole agonists of the human secretin receptor.SLAS discovery : advancing life sciences R & D · 2024Article
- Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.Biochemistry · 2023Article
- Article
- Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.SLAS discovery : advancing life sciences R & D · 2022Article
- Secretin Amino-Terminal Structure-Activity Relationships and Complementary Mutagenesis at the Site of Docking to the Secretin Receptor.Molecular pharmacology · 2022Article
- Oxytocin and secretin receptors - implications for dry eye syndrome and ocular pain.Frontiers in ophthalmology · 2022Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a high-throughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs. Here we outline a comprehensive study comprising a structure-activity series based on commercially available analogs of the three hit scaffold sets A (2-sulfonyl pyrimidines), B (2-mercapto pyrimidines) and C (2-amino pyrimidines), which revealed determinants of activity, cooperativity and specificity. Structural optimization of original hits resulted in analog B2, which substantially enhances signaling of truncated secretin peptides and prolongs residence time of labeled secretin up to 13-fold in a dose-dependent manner. Furthermore, we found that investigated compounds display structural similarity to positive allosteric modulators (PAMs) active at the glucagon-like peptide-1 receptor (GLP-1R), and we were able to confirm cross-recognition of that receptor by a subset of analogs. Studies using SCTR and GLP-1R mutants revealed that scaffold A, but not B and C, likely acts via two distinct mechanisms, one of which constitutes covalent modification of Cys-347
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.