The design, synthesis and testing of desoxy-CBD: further evidence for a region of steric interference at the cannabinoid receptor.
Cannabidiol CBD, a non-psychoactive constituent of marihuana, has been reported to possess essentially no affinity for cannabinoid CB1 receptor binding sites in the brain. Our hypothesis concerning CBD's lack of affinity for the cannabinoid CB1 receptor is that CBD is not capable of clearing a region of steric interference at the CB1 receptor and thereby not able to bind to this receptor. We have previously characterized this region of steric interference at the CB1 receptor [P.H. Reggio, A.M. Panu, S. Miles J. Med. Chem. 36, 1761-1771 (1993)] in three dimensions using the Active Analog Approach. We report here a conformational analysis of CBD which, in turn, led to the design of a new analog, desoxy-CBD. Modeling results for desoxy-CBD predict that this compound is capable of clearing the region of steric interference by expending 3.64 kcal/mol of energy in contrast to the 12.39 kcal/mol expenditure required by CBD. Desoxy-CBD was synthesized by condensation of 3-pentylphenol with p-mentha-2,8-dien-1-ol mediated by DMF-dineopental acetal. Desoxy-CBD was found to behave as a partial agonist in the mouse vas deferens assay, an assay which is reported to detect the presence of cannabinoid receptors. The compound produced a concentration related inhibition of electrically-evoked contractions of the mouse vas deferens, possessing an IC50 of 30.9 nM in this assay. Taken together, these results support the hypothesis of the existence of a region of steric interference at the CB1 receptor. While the energy expenditure to clear this region was too high for the parent compound, CBD, the removal of the C6' hydroxyl of CBD produced a molecule (desoxy-CBD) able to clear this region and produce activity, albeit at a reduced level.
Reggio
P H
PH
Department of Chemistry, Kennesaw State College, Marietta, GA 30061, USA.
Bramblett
R D
RD
Yuknavich
H
H
Seltzman
H H
HH
Fleming
D N
DN
Fernando
S R
SR
Stevenson
L A
LA
Pertwee
R G
RG
D000818:Animals; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C094026:desoxycannabidiol; D002185:Cannabidiol