Probing the Carboxyester Side Chain in Controlled Deactivation (−)-Δ8-Tetrahydrocannabinols

DSpace/Manakin Repository

Probing the Carboxyester Side Chain in Controlled Deactivation (−)-Δ8-Tetrahydrocannabinols

Citable link to this page

 

 
Title: Probing the Carboxyester Side Chain in Controlled Deactivation (−)-Δ8-Tetrahydrocannabinols
Author: Nikas, Spyros P.; Sharma, Rishi; Paronis, Carol A.; Kulkarni, Shashank; Thakur, Ganesh A.; Hurst, Dow; Wood, JodiAnne T.; Gifford, Roger S.; Rajarshi, Girija; Liu, Yingpeng; Raghav, Jimit Girish; Guo, Jason Jianxin; Järbe, Torbjörn U.C.; Reggio, Patricia H.; Bergman, Jack; Makriyannis, Alexandros

Note: Order does not necessarily reflect citation order of authors.

Citation: Nikas, S. P., R. Sharma, C. A. Paronis, S. Kulkarni, G. Thakur, D. Hurst, J. T. Wood, et al. 2014. “Probing the Carboxyester Side Chain in Controlled Deactivation (−)-Δ8-Tetrahydrocannabinols.” Journal of Medicinal Chemistry 58 (2): 665-681. doi:10.1021/jm501165d. http://dx.doi.org/10.1021/jm501165d.
Full Text & Related Files:
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.
Published Version: doi:10.1021/jm501165d
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306527/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993569
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters