A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB(2) receptor.
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 CB(1) 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 NaBH(4) 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(1) receptor (K(i) > 970 nM), but both have moderately high affinity for the CB(2) receptor (K(i) < 60 nM).
Huffman
J W
JW
Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-1905, USA. huffman@clemson.edu
Lu
J
J
Hynd
G
G
Wiley
J L
JL
Martin
B R
BR
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003511:Cyclohexanols; D006801:Humans; D008024:Ligands; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D008024:Ligands; D011728:Pyridones; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C036088:CP 47497