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 μ 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 μ-affinities, with (±)-4 being almost as potent as (−)-morphine; while the trans 3′-methyl analog (±)-5 remained a weak μ-binder. Energy calculations and nmr data indicated that compounds 2-4 favor phenyl-axial conformations, while compounds 1 and 5 favor phenyl-equatorial conformations.