Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity
Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of medicinal chemistry - 63(2020), 10 vom: 28. Mai, Seite 5119-5138 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Norwood, Verrill M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.10.2020 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.9b01924 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM305124102 |
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| 520 | |a Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Shi, Guqin |e verfasserin |4 aut | |
| 700 | 1 | |a Ratnayake, Ranjala |e verfasserin |4 aut | |
| 700 | 1 | |a Rocca, James R |e verfasserin |4 aut | |
| 700 | 1 | |a Abboud, Khalil A |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chenglong |e verfasserin |4 aut | |
| 700 | 1 | |a Luesch, Hendrik |e verfasserin |4 aut | |
| 700 | 1 | |a McLaughlin, Jay P |e verfasserin |4 aut | |
| 700 | 1 | |a Huigens, Robert W |c 3rd |e verfasserin |4 aut | |
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