Structure-activity relationships for 1',1'-dimethylalkyl-Delta8-tetrahydrocannabinols.
A series of 1',1'-dimethylalkyl-Delta(8)-tetrahydrocannabinol analogues with C-3 side chains of 2-12 carbon atoms has been synthesized and their in vitro and in vivo pharmacology has been evaluated. The lowest member of the series, 1',1'-dimethylethyl-Delta(8)-THC (8, n=0) has good affinity for the CB(1) receptor, but is inactive in vivo. The dimethylpropyl (8, n=1) through dimethyldecyl (8, n=8) all have high affinity for the CB(1) receptor and are full agonists in vivo. 1',1'-Dimethylundecyl-Delta(8)-THC (8, n=9) has significant affinity for the receptor (K(i)=25.8+/-5.8 nM), but has reduced potency in vivo. The dodecyl analogue (8, n=10) has little affinity for the CB(1) receptor and is inactive in vivo. A quantitative structure-activity relationship study of the side chain region of these compounds is consistent with the concept that for optimum affinity and potency the side chain must be of a length which will permit its terminus to loop back in proximity to the phenolic ring of the cannabinoid.
Huffman
John W
JW
Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA. huffman@clemson.edu
Miller
John R A
JR
Liddle
John
J
Yu
Shu
S
Thomas
Brian F
BF
Wiley
Jenny L
JL
Martin
Billy R
BR
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003511:Cyclohexanols / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011930:Reaction Time; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects*; D013055:Spectrophotometry, Infrared
D003511:Cyclohexanols; D007202:Indicators and Reagents; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol