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Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist
[Image: see text] Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testin...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10125376/ https://www.ncbi.nlm.nih.gov/pubmed/37102164 http://dx.doi.org/10.1021/acsbiomedchemau.2c00016 |
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author | Mehrotra, Suneet Lam, Sebastian Glenn, Elizabeth Hymel, David Sanford, Christina A. Liu, Qingyuan Herich, John Wulff, Birgitte S. Meek, Thomas H. |
author_facet | Mehrotra, Suneet Lam, Sebastian Glenn, Elizabeth Hymel, David Sanford, Christina A. Liu, Qingyuan Herich, John Wulff, Birgitte S. Meek, Thomas H. |
author_sort | Mehrotra, Suneet |
collection | PubMed |
description | [Image: see text] Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissue-specific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion. With these considerations in mind, the availability of potent, selective NMU compounds with appropriate pharmacokinetic profiles would advance the capabilities of investigators undertaking such efforts. Here, we evaluate a recently reported NMUR2-selective peptide (compound 17) for its in vitro potency (mouse and human), binding affinity, murine pharmacokinetic properties, and in vivo effects. Despite being designed as an NMUR2 agonist, our results show compound 17 unexpectedly binds but does not have functional activity on NMUR1, thereby acting as an R1 antagonist while simultaneously being a potent NMUR2 agonist. Furthermore, evaluation of compound 17 across all known and orphan G-protein-coupled receptors demonstrates multiple receptor partners beyond NMUR2/R1 binding. These properties need to be appreciated for accurate interpretation of results generated using this molecule and may limit the broader ability of this particular entity in disentangling the physiological role of NMU receptor biology. |
format | Online Article Text |
id | pubmed-10125376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-101253762023-04-25 Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist Mehrotra, Suneet Lam, Sebastian Glenn, Elizabeth Hymel, David Sanford, Christina A. Liu, Qingyuan Herich, John Wulff, Birgitte S. Meek, Thomas H. ACS Bio Med Chem Au [Image: see text] Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissue-specific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion. With these considerations in mind, the availability of potent, selective NMU compounds with appropriate pharmacokinetic profiles would advance the capabilities of investigators undertaking such efforts. Here, we evaluate a recently reported NMUR2-selective peptide (compound 17) for its in vitro potency (mouse and human), binding affinity, murine pharmacokinetic properties, and in vivo effects. Despite being designed as an NMUR2 agonist, our results show compound 17 unexpectedly binds but does not have functional activity on NMUR1, thereby acting as an R1 antagonist while simultaneously being a potent NMUR2 agonist. Furthermore, evaluation of compound 17 across all known and orphan G-protein-coupled receptors demonstrates multiple receptor partners beyond NMUR2/R1 binding. These properties need to be appreciated for accurate interpretation of results generated using this molecule and may limit the broader ability of this particular entity in disentangling the physiological role of NMU receptor biology. American Chemical Society 2022-05-27 /pmc/articles/PMC10125376/ /pubmed/37102164 http://dx.doi.org/10.1021/acsbiomedchemau.2c00016 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Mehrotra, Suneet Lam, Sebastian Glenn, Elizabeth Hymel, David Sanford, Christina A. Liu, Qingyuan Herich, John Wulff, Birgitte S. Meek, Thomas H. Unanticipated Characteristics of a Selective, Potent Neuromedin-U Receptor 2 Agonist |
title | Unanticipated Characteristics of a Selective, Potent
Neuromedin-U Receptor 2 Agonist |
title_full | Unanticipated Characteristics of a Selective, Potent
Neuromedin-U Receptor 2 Agonist |
title_fullStr | Unanticipated Characteristics of a Selective, Potent
Neuromedin-U Receptor 2 Agonist |
title_full_unstemmed | Unanticipated Characteristics of a Selective, Potent
Neuromedin-U Receptor 2 Agonist |
title_short | Unanticipated Characteristics of a Selective, Potent
Neuromedin-U Receptor 2 Agonist |
title_sort | unanticipated characteristics of a selective, potent
neuromedin-u receptor 2 agonist |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10125376/ https://www.ncbi.nlm.nih.gov/pubmed/37102164 http://dx.doi.org/10.1021/acsbiomedchemau.2c00016 |
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