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The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor
The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulato...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10408732/ https://www.ncbi.nlm.nih.gov/pubmed/37058425 http://dx.doi.org/10.1213/ANE.0000000000006461 |
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author | Arias, Hugo R. Tae, Han-Shen Micheli, Laura Yousuf, Arsalan Manetti, Dina Romanelli, Maria Novella Ghelardini, Carla Adams, David J. Di Cesare Mannelli, Lorenzo |
author_facet | Arias, Hugo R. Tae, Han-Shen Micheli, Laura Yousuf, Arsalan Manetti, Dina Romanelli, Maria Novella Ghelardini, Carla Adams, David J. Di Cesare Mannelli, Lorenzo |
author_sort | Arias, Hugo R. |
collection | PubMed |
description | The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca(V)2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497’s effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca(V)2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca(V)2.2 channel can be ruled out. |
format | Online Article Text |
id | pubmed-10408732 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-104087322023-08-09 The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor Arias, Hugo R. Tae, Han-Shen Micheli, Laura Yousuf, Arsalan Manetti, Dina Romanelli, Maria Novella Ghelardini, Carla Adams, David J. Di Cesare Mannelli, Lorenzo Anesth Analg 38 The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca(V)2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497’s effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca(V)2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca(V)2.2 channel can be ruled out. Lippincott Williams & Wilkins 2023-04-14 2023-09 /pmc/articles/PMC10408732/ /pubmed/37058425 http://dx.doi.org/10.1213/ANE.0000000000006461 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | 38 Arias, Hugo R. Tae, Han-Shen Micheli, Laura Yousuf, Arsalan Manetti, Dina Romanelli, Maria Novella Ghelardini, Carla Adams, David J. Di Cesare Mannelli, Lorenzo The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title | The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title_full | The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title_fullStr | The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title_full_unstemmed | The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title_short | The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor |
title_sort | antinociceptive activity of (e)-3-(thiophen-2-yl)-n-(p-tolyl)acrylamide in mice is reduced by (e)-3-(furan-2-yl)-n-methyl-n-(p-tolyl)acrylamide through opposing modulatory mechanisms at the α7 nicotinic acetylcholine receptor |
topic | 38 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10408732/ https://www.ncbi.nlm.nih.gov/pubmed/37058425 http://dx.doi.org/10.1213/ANE.0000000000006461 |
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