Publications by authors named "Jennifer M Cook"

4 Publications

  • Page 1 of 1

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.

Cell Mol Life Sci 2017 04 16;74(7):1335-1345. Epub 2016 Nov 16.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC, MC, and MC receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r-/- mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.
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http://dx.doi.org/10.1007/s00018-016-2419-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346439PMC
April 2017

Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors.

J Biomol Screen 2013 Jun 8;18(5):599-609. Epub 2013 Feb 8.

Medical Research Council Technology, Centre for Therapeutic Discovery, London, UK.

A variety of G-protein-coupled receptor (GPCR) screening technologies have successfully partnered a number of GPCRs with their cognate ligands. GPCR-mediated β-arrestin recruitment is now recognized as a distinct intracellular signaling pathway, and ligand-receptor interactions may show a bias toward β-arrestin over classical GPCR signaling pathways. We hypothesized that the failure to identify native ligands for the remaining orphan GPCRs may be a consequence of biased β-arrestin signaling. To investigate this, we assembled 10 500 candidate ligands and screened 82 GPCRs using PathHunter β-arrestin recruitment technology. High-quality screening assays were validated by the inclusion of liganded receptors and the detection and confirmation of these established ligand-receptor pairings. We describe a candidate endogenous orphan GPCR ligand and a number of novel surrogate ligands. However, for the majority of orphan receptors studied, measurement of β-arrestin recruitment did not lead to the identification of cognate ligands from our screening sets. β-Arrestin recruitment represents a robust GPCR screening technology, and ligand-biased signaling is emerging as a therapeutically exploitable feature of GPCR biology. The identification of cognate ligands for the orphan GPCRs and the extent to which receptors may exist to preferentially signal through β-arrestin in response to their native ligand remain to be determined.
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http://dx.doi.org/10.1177/1087057113475480DOI Listing
June 2013

Considerations for percutaneous absorption.

Int J Pharm Compd 2010 Jul-Aug;14(4):301-4

Spectrum Pharmacy Products Pharmacy Technical Services, Tucson, Arizona.

Percutaneous absorption is affected by numerous factors. Whether they are internal or external factors, the compounding pharmacist must collectively consider these variables in order to provide a safe and effective topical preparation for the patient. By considering the physiochemical and dermal factors that affect percutaneous absorption of a medication, an effective topical medication can be formulated to treat the patient's specific indication. Furthermore, this article will review the background information necessary to formulate transdermal prescriptions for their patients.
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February 2015

Uranium speciation in moorland river water samples: a comparison of experimental results and computer model predictions.

J Environ Monit 2005 Jun 20;7(6):559-67. Epub 2005 May 20.

School of Earth, Ocean and Environmental Sciences, University of Plymouth, Devon, UK.

An on-line method has been developed for separating inorganic and organic bound uranium species present in river water samples. The method utilised a small chelating resin (Hyphan) column incorporated into the sample introduction manifold of an ICP-MS instrument. The method was evaluated for samples from rivers on Dartmoor (Devon, UK), an area of granite overlain with peat bogs. The results indicate that organic-uranium species form a major proportion (80%) of the total dissolved uranium present. Further work with synthetic water samples indicated that the level of dissolved organic carbon played a greater role in determining the level of organic-uranium species than did sample pH. Computer models for the water samples were constructed using the WHAM program (incorporating uranium data from the Nuclear Energy Agency Thermochemical Database project) in order to predict the levels of organic-uranium species that would form. By varying the proportion of humic and fulvic acids used in the humic component, predictions within 10% of the experimental results were obtained. The program did exhibit a low bias at higher pH values (7.5) and low organic carbon concentrations (0.5 microg ml(-1)), but under the natural conditions prevalent in the Dartmoor water samples, the model predictions were successful.
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http://dx.doi.org/10.1039/b415287eDOI Listing
June 2005
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