Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'.
Earlier work from our laboratories has provided evidence for the existence of a subsite within the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the benzylic side chain position of classical cannabinoids. The existence and stereochemical features of this subsite have now been probed through the synthesis of a novel series of (-)-Delta(8)-tetrahydrocannabinol analogues bearing C1'-ring substituents. Of the compounds described here, those with C1'-dithiolane (1c), C1'-dioxolane (2d), and cyclopentyl (2a) substituents exhibited the highest affinities for CB1 and CB2. We used molecular modeling approaches to better define the stereochemical limits of the putative subsite. In vitro pharmacological testing found 1c to be a potent CB1 agonist.
Papahatjis
Demetris P
DP
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vass. Constantinou, Athens 116-35 Greece. dpapah@eie.gr
Nikas
Spyros P
SP
Kourouli
Therapia
T
Chari
Ravi
R
Xu
Wei
W
Pertwee
Roger G
RG
Makriyannis
Alexandros
A
D000818:Animals; D001665:Binding Sites; D002186:Cannabinoids / Q000378:metabolism*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D013154:Spleen / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D002186:Cannabinoids; C469526:Cnr2 protein, rat; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol