Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074
Selective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, ther...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/17/5672 |
| _version_ | 1797494073788989440 |
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| author | George Amato Vineetha Vasukuttan Danni Harris Lucas Laudermilk Jennifer Lucitti Scott Runyon Rangan Maitra |
| author_facet | George Amato Vineetha Vasukuttan Danni Harris Lucas Laudermilk Jennifer Lucitti Scott Runyon Rangan Maitra |
| author_sort | George Amato |
| collection | DOAJ |
| description | Selective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, there has been limited reports on the development of partial agonists. Partial agonists targeting peripheral CBRs may have desirable pharmacological profiles while not producing centrally mediated dissociative effects. Bayer reported that BAY 59-3074 is a CNS penetrant partial agonist of both CB1 and CB2 receptors with efficacy in rat models of neuropathic and inflammatory pain. In this report, we demonstrate our efforts to synthesize analogs that would favor peripheral selectivity, while maintaining partial agonism of CB1. Our efforts led to the identification of a novel compound, which is a partial agonist of the human CB1 (hCB1) receptor with vastly diminished brain exposure compared to BAY 59-3074. |
| first_indexed | 2024-03-10T01:29:05Z |
| format | Article |
| id | doaj.art-c6b92781d8634a3b8718e9bbf0b5f6e7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:29:05Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c6b92781d8634a3b8718e9bbf0b5f6e72023-11-23T13:46:12ZengMDPI AGMolecules1420-30492022-09-012717567210.3390/molecules27175672Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074George Amato0Vineetha Vasukuttan1Danni Harris2Lucas Laudermilk3Jennifer Lucitti4Scott Runyon5Rangan Maitra6Center for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USACenter for Drug Discovery, RTI International, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USASelective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, there has been limited reports on the development of partial agonists. Partial agonists targeting peripheral CBRs may have desirable pharmacological profiles while not producing centrally mediated dissociative effects. Bayer reported that BAY 59-3074 is a CNS penetrant partial agonist of both CB1 and CB2 receptors with efficacy in rat models of neuropathic and inflammatory pain. In this report, we demonstrate our efforts to synthesize analogs that would favor peripheral selectivity, while maintaining partial agonism of CB1. Our efforts led to the identification of a novel compound, which is a partial agonist of the human CB1 (hCB1) receptor with vastly diminished brain exposure compared to BAY 59-3074.https://www.mdpi.com/1420-3049/27/17/5672CB1cannabinoidperipheralCB2partialagonist |
| spellingShingle | George Amato Vineetha Vasukuttan Danni Harris Lucas Laudermilk Jennifer Lucitti Scott Runyon Rangan Maitra Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 Molecules CB1 cannabinoid peripheral CB2 partial agonist |
| title | Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 |
| title_full | Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 |
| title_fullStr | Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 |
| title_full_unstemmed | Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 |
| title_short | Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074 |
| title_sort | structure activity relationship development efforts towards peripherally selective analogs of the cannabinoid receptor partial agonist bay 59 3074 |
| topic | CB1 cannabinoid peripheral CB2 partial agonist |
| url | https://www.mdpi.com/1420-3049/27/17/5672 |
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