Discovery of Peripheral κ-Opioid Receptor Agonists as Novel Analgesics

Abstract

κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

AMPK activation attenuates inflammatory pain through inhibiting NF-κB activation and IL-1β expression

“…As an activator of AMPK, metformin may be used for treating inflammatory pain conditions. In addition, the upstream signaling of AMPK, cannabinoid receptor 1/2 and κ-opioid receptors, is known to participate in analgesia [47–49], and activation of these receptors promotes AMPK activation [47, 50, 51]. The cannabinoid receptor and opioid receptor agonists have many side effects, such as euphoria and addiction [52, 53].…”

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

“…Peripherally-restricted derivatives of nalfurafine are also in development by Toray Industries (Suzuki et al, 2017). There are a range of compounds with an increased number of hydrogen bond donors, including 17-hydroxy-cyclopropylmethyl (compound 8) and 10αhydroxy (compound 10) ( Fig.…”

“…3) yielding promising results. The two compounds are highly selective for the KOPr over the MOPr; in fact, compound 8 had >5,200,000 times greater selectivity for the KOPr (Suzuki et al, 2017). To assess brain penetration, the brain-plasma concentration ratio (K p,brain ) was calculated 15 min following i.v.…”

“…compound 8 was 0.11 and compound 10 was 0.07 (Suzuki et al, 2017). Finally, the compounds were tested in the acetic acid writhing model in mice, both producing dosedependent anti-allodynic effects (Suzuki et al, 2017).…”

“…compound 8 was 0.11 and compound 10 was 0.07 (Suzuki et al, 2017). Finally, the compounds were tested in the acetic acid writhing model in mice, both producing dosedependent anti-allodynic effects (Suzuki et al, 2017). These hydroxy nalfurafine compounds have encouraging results so far, however, further in vivo experiments are required to fully evaluate the antinociceptive potential and confirm there are no centrally-mediated sideeffects.…”