The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo
Copyright © 2019 Elsevier Inc. All rights reserved..
There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:181 |
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| Enthalten in: |
Pharmacology, biochemistry, and behavior - 181(2019) vom: 15. Juni, Seite 37-45 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Murnane, Kevin Sean [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.02.2020 Date Revised 01.06.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.pbb.2019.04.003 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM296194417 |
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| 100 | 1 | |a Murnane, Kevin Sean |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo |
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| 500 | |a Date Revised 01.06.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Oppong-Damoah, Aboagyewaah |e verfasserin |4 aut | |
| 700 | 1 | |a Rice, Kenner C |e verfasserin |4 aut | |
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