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μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization
Data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins.
Quantifying the association and dissociation rates of unlabelled antagonists at the muscarinic M3 receptor
It is demonstrated that a medium‐throughput competition kinetic binding assay can be used to determine accurate on and off rates of unlabelled compounds, providing the opportunity to optimise for kinetic parameters early in the drug discovery process.
In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β2 Adrenoceptor Agonist…
- C. Battram, S. Charlton, A. Trifilieff
- Biology, MedicineJournal of Pharmacology and Experimental…
- 1 May 2006
The preclinical profile of indacaterol suggests that this compound has a superior duration of action compatible with once-daily dosing in human, together with a fast onset of action and an improved cardiovascular safety profile over marketed inhaled β2 adrenoceptor agonists.
The role of kinetic context in apparent biased agonism at GPCRs
It is revealed that ‘kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias.
Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor highly expressed on human eosinophils and neutrophils.
The GPCR R527 shows pharmacological properties similar to those of the previously described 5-oxo-ETE receptor expressed on eosinophils, neutrophils, and monocytes, and this eicosanoid has been proposed to play a key role in the inflammatory response.
The Influence of Receptor Kinetics on the Onset and Duration of Action and the Therapeutic Index of NVA237 and Tiotropium
This study suggests that the 24-h duration of action of NVA237 and tiotropium is not solely the result of their slow dissociation from the M3 receptor and highlights the importance of conducting in vitro experiments in conditions reflecting those in vivo.
PPADS and suramin as antagonists at cloned P2Y‐ and P2U‐purinoceptors
- S. Charlton, Colin A. Brown, G. Weisman, J. T. Turner, L. Erb, M. Boarder
- BiologyBritish journal of pharmacology
- 1 June 1996
Suramin and PPADS show clear differences in their action at the 2 receptor types, in each case being substantially more effective as an antagonist at the P2Y‐purinoceptor than at the H‐P2U‐1321N1 cells.
Exploring the Mechanism of Agonist Efficacy: A Relationship between Efficacy and Agonist Dissociation Rate at the Muscarinic M3 Receptor
The relationship between the efficacy of seven M3 muscarinic receptor agonists and their rate of dissociation from the M3 receptor was investigated, suggesting that kinetic models incorporating the mean lifetime of specific complexes will be required to fully explain the nature of agonist efficacy.
Evidence that P2Y4 nucleotide receptors are involved in the regulation of rat aortic smooth muscle cells by UTP and ATP
- S. Harper, T. E. Webb, S. Charlton, L. Ng, M. Boarder
- BiologyBritish journal of pharmacology
- 1 June 1998
In SHR derived cultured aortic smooth muscle cells, PLC responses to extracellular UTP and ATP are predominantly at P2Y4 receptors, and suggest that these receptors are coupled to mitogenesis via p42/p44 MAPK.
Long‐lasting target binding and rebinding as mechanisms to prolong in vivo drug action
Simulations reveal that these latter phenomena become especially influential when there is no longer sufficient free drug around to maintain high levels of receptor occupancy, as the rate of free drug elimination from the effect compartment is also a key influencing factor.