The highly G protein-biased mu opioid agonist displays buprenorphine-like efficacy in primates

SR-17018 was identified as a highly G protein-biased signaling mu opioid peptide (MOP) receptor agonist with an improved side-effect profile in mice; however, its functional profile in translationally relevant primate models remains unknown. Using rhesus monkeys ( Macaca mulatta ), we compared the in vivo effects of spinal and systemic SR-17018 with MOP agonists spanning a range of intrinsic efficacies—DAMGO, morphine, heroin, and buprenorphine—using behavioral assays for nociception, itch-scratching, operant reinforcement, and respiratory depression. Following intrathecal administration, SR-17018 (30–300 µg), buprenorphine (3–10 µg), morphine (10–30 µg), and DAMGO (1–3 µg) each dose-dependently attenuated capsaicin-induced thermal allodynia, although SR-17018 required substantially higher doses than morphine or DAMGO to achieve comparable antinociception. In contrast to DAMGO and morphine, which elicited robust itch-scratching responses, intrathecal SR-17018 and buprenorphine produced only mild scratching, indicative of low MOP receptor efficacy. In the intravenous drug self-administration assay under a progressive-ratio schedule, heroin (0.3–10 μg/kg/infusion) generated greater reinforcing strength than either SR-17018 (3–30 μg/kg/infusion) or buprenorphine (1–10 μg/kg/infusion) which generated greater reinforcing strength than saline. These findings demonstrate that SR-17018 exhibits an in vivo functional profile consistent with low MOP receptor efficacy rather than a high-efficacy agonist, closely resembling the partial agonist buprenorphine across primate assays with established clinical and translational relevance. Our results support the conclusion that the reduced intrinsic efficacy of SR-17018 likely underlies both its attenuated adverse-effect profile and its diminished abuse liability, emphasizing the importance of primate models for defining the translational properties of novel opioid ligands.