Adamantyl cannabinoids: a novel class of cannabinergic ligands.
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 Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-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.
Lu
Dai
D
Center for Drug Discovery, Northeastern University, 116 Mugar Life Sciences Building, Boston, Massachusetts 02115, USA.
Meng
Zhaoxing
Z
Thakur
Ganesh A
GA
Fan
Pusheng
P
Steed
John
J
Tartal
Cindy L
CL
Hurst
Dow P
DP
Reggio
Patricia H
PH
Deschamps
Jeffrey R
JR
Parrish
Damon A
DA
George
Clifford
C
Järbe
Torbjörn U C
TU
Lamb
Richard J
RJ
Makriyannis
Alexandros
A
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D013759:Dronabinol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol; D000218:Adamantane