Structure-activity relationships for 1 ',1 '-dimethylalkyl-Delta(8)-tetrahydrocannabinols
Huffman, J. W., Miller, J. R. A., Liddle, J., Yu, S., Thomas, B., Wiley, J., & Martin, B. R. (2003). Structure-activity relationships for 1 ',1 '-dimethylalkyl-Delta(8)-tetrahydrocannabinols. Bioorganic and Medicinal Chemistry, 11(7), 1397-1410. DOI: 10.1016/S0968-0896(02)00649-1
A series of 1?,1?-dimethylalkyl-?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-?8-THC (8, n=0) has good affinity for the CB1 receptor, but is inactive in vivo. The dimethylpropyl (8, n=1) through dimethyldecyl (8, n=8) all have high affinity for the CB1 receptor and are full agonists in vivo. 1?,1?-Dimethylundecyl-?8-THC (8, n=9) has significant affinity for the receptor (Ki=25.8±5.8 nM), but has reduced potency in vivo. The dodecyl analogue (8, n=10) has little affinity for the CB1 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.