A pyridone analogue (5) of the potent bicyclic cannabinoid CP 47,497 (6) has been synthesized as a model for one conformational isomer of anandamide and to test the hypothesis that an amide carbonyl may serve as a hydrogen bond acceptor in interactions with the CB1 cannabinoid receptor. Pyridone 5 was synthesized from 6-bromo-2-methoxypyridine (10) by palladium catalyzed coupling with 1-pentyne to provide 11. Catalytic hydrogenation of 11 and hydrolysis to pyridone 13 followed by N-alkylation gave 1-propyl-6-pentyl-2-pyridone (15). Bromination of 15 gave dibromide 18, which underwent Heck coupling with cyclohex-2-en-1-one to give enone 19, Catalytic hydrogenation of 19 gave ketone 20 which was reduced using NaBH4 to alcohol 5. Reduction of 20 with K-Selectride gave the axial epimer of 5 (21). Neither alcohol 5 nor 21 have significant affinity for the CB, receptor (K-i > 970 nM), but both have moderately high affinity for the CB2 receptor (K-i < 60 nM). (C) 2001 Elsevier Science Ltd. All rights reserved
A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB2 receptor
Huffman, JW., Lu, JZ., Hynd, G., Wiley, J., & Martin, BR. (2001). A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB2 receptor. Bioorganic and Medicinal Chemistry, 9(11), 2863-2870.