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Your search keyword '"Wigglesworth, Mark J"' showing total 24 results
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24 results on '"Wigglesworth, Mark J"'

7. Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors

Author

Routledge, Sarah J., Simms, John, Clark, Ashley, Yeung, Ho Yan, Wigglesworth, Mark J., Dickerson, Ian M., Kitchen, Philip, Ladds, Graham, Poyner, David R., Routledge, Sarah J., Simms, John, Clark, Ashley, Yeung, Ho Yan, Wigglesworth, Mark J., Dickerson, Ian M., Kitchen, Philip, Ladds, Graham, and Poyner, David R.

Abstract

Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at the CGRP receptor, a heterodimer of calcitonin receptor like-receptor (CLR), a family B G protein-coupled receptor (GPCR) and receptor activity modifying protein 1 (RAMP1). We extend these observations to show that it selectively enhances CGRP receptor coupling to Gs but not Gq or pERK activation. At other family B GPCRs, it enhances cAMP production at the calcitonin, corticotrophin releasing factor type 1a and glucagon-like peptide type 2 receptors with their cognate ligands but not at the adrenomedullin type 1 (AM1), gastric inhibitory peptide and glucagon-like peptide type 1 receptors, all expressed in transfected HEK293S cells. However, there is also cell-line variability as RCP did not enhance cAMP production at the endogenous calcitonin receptor in HEK293T cells and it has previously been reported that it is active on the AM1 receptor expressed on NIH3T3 cells. RCP appears to behave as a positive allosteric modulator at coupling a number of family B GPCRs to Gs, albeit in a manner that is regulated by cell-specific factors. It may exert its effects at the interface between the 2nd intracellular loop of the GPCR and Gs, although there is likely to be some overlap between this location and that occupied by the C-terminus of RAMPs if they bind to the GPCRs.

Published
2020

12. Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74

Author

Miller, Philip S., Barwell, James, Poyner, David R., Wigglesworth, Mark J., Garland, Stephen L., Donnelly, Dan, Miller, Philip S., Barwell, James, Poyner, David R., Wigglesworth, Mark J., Garland, Stephen L., and Donnelly, Dan

Abstract

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affinity for MK-0974. In addition, we confirm that the Trp-74-Lys mutation at human RAMP1 reduces BIBN4096BS affinity by over 300-fold and show for the first time a similar effect for MK-0974 affinity. The data suggest that the non-peptide antagonists occupy a binding site close to the interface of the N-terminal domains of CLR and RAMP1.

Published
2010

14. Novel Spirotetracyclic Zwitterionic Dual H1/5-HT2A Receptor Antagonists for the Treatment of Sleep Disorders

Author

Gianotti, Massimo, primary, Botta, Maurizio, additional, Brough, Stephen, additional, Carletti, Renzo, additional, Castiglioni, Emiliano, additional, Corti, Corrado, additional, Dal-Cin, Michele, additional, Delle Fratte, Sonia, additional, Korajac, Denana, additional, Lovric, Marija, additional, Merlo, Giancarlo, additional, Mesic, Milan, additional, Pavone, Francesca, additional, Piccoli, Laura, additional, Rast, Slavko, additional, Roscic, Maja, additional, Sava, Anna, additional, Smehil, Mario, additional, Stasi, Luigi, additional, Togninelli, Andrea, additional, and Wigglesworth, Mark J., additional

Published
2010
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15. Towards the Discovery of New Hypnotic Agents: Synthesis and Preliminary Pharmacological Evaluation of a Novel Class of Dibenzo[a,d]cycloheptene Derivatives

Author

Castiglioni, Emiliano, primary, Di Fabio, Romano, additional, Togninelli, Andrea, additional, Brough, Stephen, additional, Brown, Fiona, additional, Cin, Michele Dal, additional, Gianotti, Massimo, additional, Marchioro, Carla, additional, Merlo, Giancarlo, additional, Spinosa, Raffaella, additional, Wigglesworth, Mark J., additional, and Botta, Maurizio, additional

Published
2010
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20. The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids

Author

Brown, Andrew J., primary, Goldsworthy, Susan M., additional, Barnes, Ashley A., additional, Eilert, Michelle M., additional, Tcheang, Lili, additional, Daniels, Dion, additional, Muir, Alison I., additional, Wigglesworth, Mark J., additional, Kinghorn, Ian, additional, Fraser, Neil J., additional, Pike, Nicholas B., additional, Strum, Jay C., additional, Steplewski, Klaudia M., additional, Murdock, Paul R., additional, Holder, Julie C., additional, Marshall, Fiona H., additional, Szekeres, Philip G., additional, Wilson, Shelagh, additional, Ignar, Diane M., additional, Foord, Steve M., additional, Wise, Alan, additional, and Dowell, Simon J., additional

Published
2003
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22. Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors

Author

Routledge, Sarah J, Simms, John, Clark, Ashley, Yeung, Ho Yan, Wigglesworth, Mark J, Dickerson, Ian M, Kitchen, Philip, Ladds, Graham, and Poyner, David R

Subjects
Accessory protein, Allosteric modulator, Calcitonin Gene-Related Peptide, Peptide Hormones, Calcitonin Receptor-Like Protein, Membrane Proteins, Ligands, 3. Good health, Receptor Activity-Modifying Protein 1, Receptors, G-Protein-Coupled, Adrenomedullin, HEK293 Cells, G protein coupling, Cyclic AMP, Animals, Humans, CGRP, hormones, hormone substitutes, and hormone antagonists, GPCR signalling, Adaptor Proteins, Signal Transducing, Signal Transduction
Abstract

Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at the CGRP receptor, a heterodimer of calcitonin receptor like-receptor (CLR), a family B G protein-coupled receptor (GPCR) and receptor activity modifying protein 1 (RAMP1). We extend these observations to show that it selectively enhances CGRP receptor coupling to Gs but not Gq or pERK activation. At other family B GPCRs, it enhances cAMP production at the calcitonin, corticotrophin releasing factor type 1a and glucagon-like peptide type 2 receptors with their cognate ligands but not at the adrenomedullin type 1 (AM1), gastric inhibitory peptide and glucagon-like peptide type 1 receptors, all expressed in transfected HEK293S cells. However, there is also cell-line variability as RCP did not enhance cAMP production at the endogenous calcitonin receptor in HEK293T cells and it has previously been reported that it is active on the AM1 receptor expressed on NIH3T3 cells. RCP appears to behave as a positive allosteric modulator at coupling a number of family B GPCRs to Gs, albeit in a manner that is regulated by cell-specific factors. It may exert its effects at the interface between the 2nd intracellular loop of the GPCR and Gs, although there is likely to be some overlap between this location and that occupied by the C-terminus of RAMPs if they bind to the GPCRs.

24. Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders

Author

Gianotti, Massimo, Corti, Corrado, Fratte, Sonia Delle, Di Fabio, Romano, Leslie, Colin P., Pavone, Francesca, Piccoli, Laura, Stasi, Luigi, and Wigglesworth, Mark J.

Subjects
*IMIDES, *HISTAMINE, *SLEEP disorders treatment, *PROPIONIC acid, *TRYPTAMINE, *HYPNOTICS
Abstract

Abstract: A novel imidazobenzazepine template (5a) with potent dual H1/5-HT2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R1-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H1/5-HT2A receptor antagonist activities and good developability profiles. [ABSTRACT FROM AUTHOR]

Published
2010
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