scholarly journals Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists

MedChemComm ◽  
2017 ◽  
Vol 8 (10) ◽  
pp. 1897-1908 ◽  
Author(s):  
Kiran S. Toti ◽  
Shanu Jain ◽  
Antonella Ciancetta ◽  
Ramachandran Balasubramanian ◽  
Saibal Chakraborty ◽  
...  
Keyword(s):  
Ring System ◽  
Calcium Mobilization ◽  
Pyrimidine Nucleotides ◽  
Receptor Agonists ◽  
P2y6 Receptor ◽  
Calcium Mobilization Assay

Uracil nucleotides containing a south-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay.

scholarly journals 68Ga-Radiolabeling and Pharmacological Characterization of a Kit-Based Formulation of the Gastrin-Releasing Peptide Receptor (GRP-R) Antagonist RM2 for Convenient Preparation of [68Ga]Ga-RM2

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1160
Author(s):  
Adrien Chastel ◽  
Delphine Vimont ◽  
Stephane Claverol ◽  
Marion Zerna ◽  
Sacha Bodin ◽  
...  
Keyword(s):  
Calcium Mobilization ◽  
Pharmacological Characterization ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Production Route ◽  
Membrane Bound ◽  
One Year ◽  
Calcium Mobilization Assay

Background: [68Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients. Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct 68Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [68Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [68Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature. Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5–5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [68Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [68Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [68Ga]Ga-RM2 displayed sub-nanomolar affinity (Kd = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [natGa]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min. Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment.

scholarly journals Enhancement of Glucose Uptake in Mouse Skeletal Muscle Cells and Adipocytes by P2Y6 Receptor Agonists

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e116203 ◽  
Author(s):  
Ramachandran Balasubramanian ◽  
Bernard Robaye ◽  
Jean-Marie Boeynaems ◽  
Kenneth A. Jacobson
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Mouse Skeletal Muscle ◽  
Receptor Agonists ◽  
P2y6 Receptor

scholarly journals Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

2008 ◽  
Vol 16 (12) ◽  
pp. 6319-6332 ◽  
Author(s):  
Hyojin Ko ◽  
Rhonda L. Carter ◽  
Liesbet Cosyn ◽  
Riccardo Petrelli ◽  
Sonia de Castro ◽  
...  
Keyword(s):  
Receptor Agonists ◽  
P2y6 Receptor

Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1

2020 ◽  
Vol 26 (1) ◽  
pp. 140-150
Author(s):  
Ann M. Decker ◽  
Kelly M. Mathews ◽  
Bruce E. Blough ◽  
Brian P. Gilmour
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Calcium Mobilization ◽  
Hit Rate ◽  
Wide Range ◽  
Trace Amine ◽  
The Central Nervous System ◽  
Calcium Mobilization Assay

The human trace amine-associated receptor 1 (hTAAR1) is a G protein-coupled receptor (GPCR) that is widely expressed in monoaminergic nuclei in the central nervous system and has therapeutic potential for multiple diseases, including drug addiction and schizophrenia. Thus, identification of novel hTAAR1 ligands is critical to advancing our knowledge of hTAAR1 function and to the development of therapeutics for a wide range of diseases. Herein we describe the development of a robust, 3-addition high-throughput screening (HTS) calcium mobilization assay using stable CHO-Gαq16-hTAAR1 cells, which functionally couple hTAAR1 to the promiscuous Gαq16 protein and thus allow signal transduction to occur through mobilization of internal calcium. Our previously established 96-well hTAAR1 assay was first miniaturized to the 384-well format and optimized to provide an assay with a Z′ factor of 0.84, which is indicative of a robust HTS assay. Using the 3-addition protocol, 22,000 compounds were screened and yielded a ~1% agonist hit rate and a ~0.2% antagonist hit rate. Of the antagonist hits, two confirmed hits are the most potent hTAAR1 antagonists identified to date (IC50 = 206 and 281 nM). While scientists have been studying hTAAR1 for years, the lack of suitable hTAAR1 antagonists has been a major roadblock for studying the basic pharmacology of hTAAR1. Thus, these new ligands will serve as valuable tools to study hTAAR1-mediated signaling mechanisms, therapeutic potential, and in vivo functions.

scholarly journals Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88

2017 ◽  
Vol 24 (1) ◽  
Author(s):  
Ann M. Decker ◽  
Elaine A. Gay ◽  
Kelly M. Mathews ◽  
Taylor C. Rosa ◽  
Tiffany L. Langston ◽  
...  
Keyword(s):  
High Throughput ◽  
Calcium Mobilization ◽  
Orphan Receptor ◽  
Development And Validation ◽  
Calcium Mobilization Assay
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