Design, Synthesis, and Pharmacological Characterization of Substituted Quinoxalines as NOP Receptor Ligands

The goal of this work was the discovery of moderate-efficacy, selective, partial agonists of the nociceptin/orphanin-FQ peptide (NOP) receptor.

A novel collection of quinoxaline-containing molecules was designed, synthesized, and assayed against NOP and mu-opioid receptors in vitro to establish the relationship between structural modification and pharmacological activity. The lead molecule identified was further assessed in vivo to determine brain penetration, analgesic effects in rodent models of pain, and motor deficits.

This SAR approach revealed that the phenyl portion of the quinoxaline is highly sensitive to modification. The unsubstituted phenyl produced a potent partial agonist (5), whereas most other substitutions created presumed antagonists or molecules that bind poorly to the receptor. Compound 5 was analgesic in rodent models of inflammatory and neuropathic pain at doses that did not produce motor deficits.

The goal of this work was achieved in discovering moderate-efficacy, selective, partial agonists of the NOP receptor. The analgesic efficacy of compound 5 is consistent with the effects of other NOP agonists in animal pain models. The partial agonist nature of 5 likely imparts a wider preclinical therapeutic index compared to full agonists.

The discovery of sunobinop (compound 5), a NOP partial agonist highly selective for NOP in vitro, was significant. Compound 5 produced antihyperalgesic efficacy in rodents and has progressed to clinical trials.