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

High affinity binding for mu and kappa 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 approximately 2000 for mu and kappa) with K(i) 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.