Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

Abstract

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of <i>N</i>-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound <b>4</b>, SLL-039) as a highly selective and potent κ opioid agonist (κ, <i>K</i>_i = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays <i>in vitro</i> and antinociceptive assays <i>in vivo</i>. The <i>in vivo</i> effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ 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.