Adamantyl cannabinoids: A novel class of cannabinergic ligands

Dai Lu, Zhaoxing Meng, Ganesh A. Thakur, Pusheng Fan, John Steed, Cindy L. Tartal, Dow P. Hurst, Patricia H. Reggio, Jeffrey R. Deschamps, Damon A. Parrish, Clifford George, Torbjörn U C Järbe, Richard J Lamb, Alexandras Makriyannis

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Δ8-THC. Our lead compound, (-)-3-(1-adamantyl)- Δ8-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.

Original languageEnglish (US)
Pages (from-to)4576-4585
Number of pages10
JournalJournal of Medicinal Chemistry
Volume48
Issue number14
DOIs
StatePublished - Jul 14 2005

Fingerprint

Cannabinoids
Cannabinoid Receptor CB1
Dronabinol
Ligands
Cannabinoid Receptor CB2
Lead compounds
Molecular modeling
Structure-Activity Relationship
Crystal structure
Binding Sites
X-Rays
X rays

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Lu, D., Meng, Z., Thakur, G. A., Fan, P., Steed, J., Tartal, C. L., ... Makriyannis, A. (2005). Adamantyl cannabinoids: A novel class of cannabinergic ligands. Journal of Medicinal Chemistry, 48(14), 4576-4585. https://doi.org/10.1021/jm058175c

Adamantyl cannabinoids : A novel class of cannabinergic ligands. / Lu, Dai; Meng, Zhaoxing; Thakur, Ganesh A.; Fan, Pusheng; Steed, John; Tartal, Cindy L.; Hurst, Dow P.; Reggio, Patricia H.; Deschamps, Jeffrey R.; Parrish, Damon A.; George, Clifford; Järbe, Torbjörn U C; Lamb, Richard J; Makriyannis, Alexandras.

In: Journal of Medicinal Chemistry, Vol. 48, No. 14, 14.07.2005, p. 4576-4585.

Research output: Contribution to journalArticle

Lu, D, Meng, Z, Thakur, GA, Fan, P, Steed, J, Tartal, CL, Hurst, DP, Reggio, PH, Deschamps, JR, Parrish, DA, George, C, Järbe, TUC, Lamb, RJ & Makriyannis, A 2005, 'Adamantyl cannabinoids: A novel class of cannabinergic ligands', Journal of Medicinal Chemistry, vol. 48, no. 14, pp. 4576-4585. https://doi.org/10.1021/jm058175c
Lu D, Meng Z, Thakur GA, Fan P, Steed J, Tartal CL et al. Adamantyl cannabinoids: A novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2005 Jul 14;48(14):4576-4585. https://doi.org/10.1021/jm058175c
Lu, Dai ; Meng, Zhaoxing ; Thakur, Ganesh A. ; Fan, Pusheng ; Steed, John ; Tartal, Cindy L. ; Hurst, Dow P. ; Reggio, Patricia H. ; Deschamps, Jeffrey R. ; Parrish, Damon A. ; George, Clifford ; Järbe, Torbjörn U C ; Lamb, Richard J ; Makriyannis, Alexandras. / Adamantyl cannabinoids : A novel class of cannabinergic ligands. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 14. pp. 4576-4585.
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