Discovery of a highly selective and potent kappa opioid receptor agonist from N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydro- northebaines with reduced central nervous system (CNS) side effects navigated by the message-address concept.

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent kappa opioid agonist (kappa, K-i = 0.47 nM, kappa/mu = 682, kappa/delta = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective kappa antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of kappa opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V118(2.63), W124(EL1), and E209(EL2).