Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity.
The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[ c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6 H-benzo[ c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity. Key pharmacophoric features of the new selective agonists include a 3-(1',1'-dimethylheptyl) side chain and a 6-oxo group on the cannabinoid tricyclic structure that characterizes this class of compounds as "cannabilactones." Our results suggest that the six-membered lactone pharmacophore is critical for CB2 receptor selectivity. Optimal receptor subtype selectivity of 490-fold and subnanomolar affinity for the CB2 receptor is exhibited by a 9-hydroxyl analog 5 (AM1714), while the 9-methoxy analog 4b (AM1710) had a 54-fold CB2 selectivity. X-ray crystallography and molecular modeling show the cannabilactones to have a planar ring conformation. In vitro testing revealed that the novel compounds are CB2 agonists, while in vivo testing of cannabilactones 4b and 5 found them to possess potent peripheral analgesic activity.
Khanolkar
Atmaram D
AD
Center for Drug Discovery, Northeastern University, 116 Mugar Hall, 360 Huntington Avenue, Boston, Massachusetts 02115-5000, USA.
Lu
Dai
D
Ibrahim
Mohab
M
Duclos
Richard I
RI
Thakur
Ganesh A
GA
Malan
T Phillip
TP
Porreca
Frank
F
Veerappan
Vijayabaskar
V
Tian
Xiaoyu
X
George
Clifford
C
Parrish
Damon A
DA
Papahatjis
Demetris P
DP
Makriyannis
Alexandros
A
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
C500323:3-(1,1-dimethyl-heptyl)-1-9-dihydroxy-benzo(c)chromen-6-one; C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D000700:Analgesics; D002867:Chromones; D007783:Lactones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2