Probing the Carboxyester Side Chain in Controlled Deactivation (−)‑Δ8‑Tetrahydrocannabinols
We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encomp...
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| Vydané v: | Journal of medicinal chemistry Ročník 58; číslo 2; s. 665 - 681 |
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| Hlavní autori: | , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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American Chemical Society
22.01.2015
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| ISSN: | 0022-2623, 1520-4804 |
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| Abstract | We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain’s polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action. |
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| AbstractList | We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain’s polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action. |
| Author | Liu, Yingpeng Paronis, Carol A Kulkarni, Shashank Wood, JodiAnne T Reggio, Patricia H Makriyannis, Alexandros Guo, Jason Jianxin Järbe, Torbjörn U.C Bergman, Jack Sharma, Rishi Gifford, Roger S Thakur, Ganesh A Rajarshi, Girija Raghav, Jimit Girish Hurst, Dow Nikas, Spyros P |
| AuthorAffiliation | Center for Drug Discovery Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences Harvard Medical School McLean Hospital University of North Carolina at Greensboro Northeastern University King Abdulaziz University |
| AuthorAffiliation_xml | – name: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences – name: Northeastern University – name: Harvard Medical School – name: McLean Hospital – name: University of North Carolina at Greensboro – name: King Abdulaziz University – name: Center for Drug Discovery |
| Author_xml | – sequence: 1 givenname: Spyros P surname: Nikas fullname: Nikas, Spyros P – sequence: 2 givenname: Rishi surname: Sharma fullname: Sharma, Rishi – sequence: 3 givenname: Carol A surname: Paronis fullname: Paronis, Carol A – sequence: 4 givenname: Shashank surname: Kulkarni fullname: Kulkarni, Shashank – sequence: 5 givenname: Ganesh A surname: Thakur fullname: Thakur, Ganesh A – sequence: 6 givenname: Dow surname: Hurst fullname: Hurst, Dow – sequence: 7 givenname: JodiAnne T surname: Wood fullname: Wood, JodiAnne T – sequence: 8 givenname: Roger S surname: Gifford fullname: Gifford, Roger S – sequence: 9 givenname: Girija surname: Rajarshi fullname: Rajarshi, Girija – sequence: 10 givenname: Yingpeng surname: Liu fullname: Liu, Yingpeng – sequence: 11 givenname: Jimit Girish surname: Raghav fullname: Raghav, Jimit Girish – sequence: 12 givenname: Jason Jianxin surname: Guo fullname: Guo, Jason Jianxin – sequence: 13 givenname: Torbjörn U.C surname: Järbe fullname: Järbe, Torbjörn U.C – sequence: 14 givenname: Patricia H surname: Reggio fullname: Reggio, Patricia H – sequence: 15 givenname: Jack surname: Bergman fullname: Bergman, Jack – sequence: 16 givenname: Alexandros surname: Makriyannis fullname: Makriyannis, Alexandros email: a.makriyannis@neu.edu |
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| Title | Probing the Carboxyester Side Chain in Controlled Deactivation (−)‑Δ8‑Tetrahydrocannabinols |
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