Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 2: 8-formamidocyclazocine analogues

High affinity binding for μ and κ opioid receptors has been observed in analogues of cyclazocine, ethylketocyclazocine and naltrexone where the prototypic (of opiates) phenolic OH group was replaced with a formamide (–NHCHO) group. For the 8-formamide analogue of cyclazocine, binding is highly enantiospecific (eudismic ratios 2000 for μ and κ) with Ki values ≤1 nM observed for the (2R,6R,11R)-isomer, (−)-4. A preliminary SAR revealed that affinity is very sensitive to substitution on the formamide appendage.