ArticleBritish journal of pharmacology2011
Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo.
Article in British journal of pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 56 citations in OpenAlex.
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- Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Functional Pyrazolo[1,5-Molecules (Basel, Switzerland) · 2021Review
- Identification of a juvenile-hormone signaling inhibitor via high-throughput screening of a chemical library.Scientific reports · 2020Article
- Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors.Pharmacology research & perspectives · 2020Article
- Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-Molecules (Basel, Switzerland) · 2020Article
- Pharmacokinetic-pharmacodynamic models that incorporate drug-target binding kinetics.Current opinion in chemical biology · 2019Review
- Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor.Scientific reports · 2019Article
- Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy.Scientific reports · 2017Article
- Understanding ligand-receptor non-covalent binding kinetics using molecular modeling.Frontiers in bioscience (Landmark edition) · 2017Review
- The Target Residence Time of Antihistamines Determines Their Antagonism of the G Protein-Coupled Histamine H1 Receptor.Frontiers in pharmacology · 2017Article
- Chronic distress and the vulnerable host: a new target for HIV treatment and prevention?Neurobehavioral HIV medicine · 2016Article
- Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors.Bioorganic & medicinal chemistry letters · 2015Article
- From G Protein-coupled Receptor Structure Resolution to Rational Drug Design.The Journal of biological chemistry · 2015Review
- Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor.Bioorganic & medicinal chemistry · 2015Article
- Corticotropin releasing hormone and imaging, rethinking the stress axis.Nuclear medicine and biology · 2015Review
- Relationship between cerebral sigma-1 receptor occupancy and attenuation of cocaine's motor stimulatory effects in mice by PD144418.The Journal of pharmacology and experimental therapeutics · 2014Article
- Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors.Nuclear medicine and biology · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeA series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF(1)) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan. EXPERIMENTAL APPROACH: A non-equilibrium binding kinetic assay was developed to determine the receptor binding kinetics of non-peptide CRF(1) antagonists. Nonlinear, mixed-effects modelling was used to obtain estimates of the compounds association and dissociation rates. We present an integrated pharmacokinetic-pharmacodynamic (PKPD) approach, whereby the time course of in vivo CRF(1) receptor binding of novel compounds can be predicted on the basis of in vitro assays. KEY
resultsThe non-competitive antagonist behaviour appeared to be correlated to the CRF(1) receptor off-rate kinetics. The integrated PKPD model suggested that, at least in a qualitative manner, the in vitro assay can be used to triage and select compounds for further in vivo investigations. CONCLUSIONS AND IMPLICATIONS: This study provides evidence for a link between ligand offset kinetics and insurmountable/non-competitive antagonism at the CRF(1) receptor. The exact molecular pharmacological nature of this association remains to be determined. In addition, we have developed a quantitative framework to study and integrate in vitro and in vivo receptor binding kinetic behaviour of CRF(1) receptor antagonists in an efficient manner in a drug discovery setting.
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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.