Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors

• Published in: Scientific reports 2023-10, Vol.13 (1), p.18164-18164, Article 18164
• Main Authors: Ide, Soichiro, Hirai, Toshitake, Muto, Takafumi, Yamakawa, Tomio, Ikeda, Kazutaka
• Format: Article
• Language: English
• Subjects: 631/154/436; 692/699/476/5; Agonists; Cyclic AMP; Drug abuse; Drug addiction; Drug overdose; Drug therapy; Humanities and Social Sciences; Morphine; multidisciplinary; Narcotics; Opioid receptors; Oral administration; Overdose; Place preference conditioning; Science; Science (multidisciplinary); Side effects; Substance use
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-45584-4

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the μ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3′,5′-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1–10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1–10 μg/kg). Nalfurafine (10 μg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.