C-alkylated spiro[benzofuran-3(2H),4'-1'-methyl-piperidine-7-ols] as potent opioids: a conformation-activity study.
Among a series of C-alkylated analogs of the weak mu opioid ligand spiro[benzofuran-3(2H),4'-1'-methylpiperidine-7-ol] (1), the 2-methyl, 2-ethyl, and cis 3'-methyl analogs, namely compounds (+/-)2, (+/-)-3, and (+/-)-4, showed much enhanced mu-affinities, with (+/-)-4 being almost as potent as (-)-morphine; while the trans 3'-methyl analog (+/-)-5 remained a weak mu-binder. Energy calculations and nmr data indicated that compounds 2-4 favor phenyl-axial conformations, while compounds 1 and 5 favor phenyl-equatorial conformations.
Tsai
Y C
YC
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
Liou
J P
JP
Liao
R
R
Cheng
C Y
CY
Tao
P L
PL
D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D010880:Piperidines; D017450:Receptors, Opioid, mu