Pharmacological evaluation of dimethylheptyl analogs of delta 9-THC: reassessment of the putative three-point cannabinoid-receptor interaction.
The basic premise underlying the cannabinoid pharmacophore is that at least three functional groups are involved in the interaction between the ligand and the receptor and that these functional groups in delta 9-THC comprise (a) C11, (b) the phenolic hydroxyl, and (c) the side chain. In order to assess the relative importance of the C11 position and the side chain, a series of C11 substituted analogs were prepared which contained a dimethylheptyl side chain. Consistent with previous studies, incorporation of a dimethylheptyl side chain dramatically enhanced both pharmacological potency in mice and receptor affinity. Incorporation of a hydroxy at C11 along with this branched side chain resulted in an extremely potent cannabinoid with ED50S of 0.01, 0.04, 0.16 and 0.04 mumol/kg in depression of spontaneous activity, reduction in body temperature, antinociception, and immobility, respectively. This compound was also very potent as a discriminative stimulus in a drug discrimination procedure and exhibited an extended duration of action. Its high affinity for the cannabinoid receptor (Ki = 400 pM) was consistent with this pharmacological potency. Incorporation of an oxo rather than a hydroxy reduced potency somewhat, although this analog was much more potent than delta 9-THC in most behavioral assays. The most striking observation was that incorporation of a carboxylic acid to form 11-nor-delta 9-THC-DMH-9-carboxylic acid did not eliminate pharmacological activity. This analog was as potent as delta 9-THC. The improbability that all three of the functional groups are interacting in a similar fashion with the receptor provides further support that the C11 position is not an essential requirement for activity. On the other hand, it is possible that substituents in the C9 region are interacting somewhere within or near the same site, but differently.
Martin
B R
BR
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Compton
D R
DR
Prescott
W R
WR
Barrett
R L
RL
Razdan
R K
RK
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001143:Arousal / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects*; D013329:Structure-Activity Relationship
D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C033189:dimethyl-heptyl tetrahydrocannabinol; D013759:Dronabinol