Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities.

Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa opioid receptor (KOR), especially those with additional mu opioid receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of meta-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound 10a. Unlike its para-positional isomer SLL-1062, where KOR activity is completely abolished, compound 10a displayed a single-digit nanomolar affinity for KOR, while its binding profiles for MOR and delta opioid receptor (DOR) were comparable to those of SLL-1062. Functional assays in vitro confirmed that compound 10a exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound 10a was further elucidated. Although compound 10a did not produce apparent antinociception in vivo, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD.