Structure-activity relationships for 1 ',1 '-dimethylalkyl-Delta(8)-tetrahydrocannabinols
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.
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