Novel adamantyl cannabinoids as CB1 receptor probes.

Abstract

In previous studies, compound 1 (AM411), a 3-(1-adamantyl) analogue of the phytocannabinoid (-)-Δ(8)-tetrahydrocannabinol (Δ(8)-THC), was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of the 1-adamantyl group at the C-3 position in a series of tricyclic cannabinoid analogues modified at the 9-northern aliphatic hydroxyl (NAH) position. Of these, 9-hydroxymethyl hexahydrocannabinol 11 (AM4054) exhibited high CB1 affinity and full agonist profile. In the cAMP assay, the 9-hydroxymethyl cannabinol analogue 24 (AM4089) had a partial agonist profile, with high affinity and moderate selectivity for rCB1 over hCB2. In vivo results in rat models of hypothermia and analgesia were congruent with in vitro data. Our in vivo data indicate that 3-(1-adamantyl) substitution, within NAH cannabinergics, imparts improved pharmacological profiles when compared to the corresponding, traditionally used 3-dimethylheptyl analogues and identifies 11 and 24 as potentially useful in vivo CB1 cannabinergic probes.

• Authors: Ganesh A Thakur, Shama Bajaj, Carol Paronis, Yan Peng, Anna L Bowman, Lawrence S Barak, Marc G Caron, Demon Parrish, Jeffrey R Deschamps, Alexandros Makriyannis
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 10 Pg. 3904-21 (May 23 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23621789 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Analgesics
• Arrestin
• Cannabinoid Receptor Agonists
• Cannabinoids
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• Cyclic AMP
• Adamantane

Topics

• Adamantane (chemical synthesis, pharmacology)
• Analgesics (chemical synthesis, pharmacology)
• Animals
• Arrestin (metabolism)
• Body Temperature (drug effects)
• Cannabinoid Receptor Agonists (chemical synthesis)
• Cannabinoids (chemical synthesis, pharmacology)
• Crystallography, X-Ray
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Female
• Hypothermia (chemically induced)
• Models, Molecular
• Pain Measurement (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (drug effects)
• Receptor, Cannabinoid, CB2 (drug effects)
• Structure-Activity Relationship