8-Carboxamidocyclazocine analogues: redefining the structure–activity relationships of 2,6-methano-3-benzazocines

Unexpectedly high affinity for opioid receptors has been observed for a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group. For μ and κ opioid receptors, the primary carboxamido derivative of cyclazocine ((±)-15) displayed high affinity (Ki=0.41 and 0.53 nM, respectively) nearly comparable to cyclazocine. A high enantiopreference ((2R,6R,11R)-) for binding was also observed. Compound (±)-15 also displayed potent antinociception activity in mice when administered icv.