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大学・研究所にある論文を検索できる 「The roles of 14-hydroxy group and D-ring structure on the affinity and their conformation of morphinan derivatives for opioid and orexin receptors」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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The roles of 14-hydroxy group and D-ring structure on the affinity and their conformation of morphinan derivatives for opioid and orexin receptors

加藤, 光貴 筑波大学 DOI:10.15068/0002005511

2022.11.17

概要

Opioidergic drugs, such as morphine (1; Figure 1), are one of the oldest drugs in human history and have been used to relieve severe pains, such as chronic and cancer pain. Opioids typically bind with three types of opioid receptors (μ, δ and κ opioid receptors; MOR, DOR, and KOR, respectively).1 These opioid receptor types were found to be involved in the analgesic effect.1 The antinociceptive effects induced by clinical opioid medications are mainly derived from the activation of MOR.2 However, MOR also produced severe side effects, such as addiction, respiratory depression, and constipation.2 DOR and KOR, on the other hand, were reported to be unrelated to addiction. Therefore, DOR and KOR agonists are expected to be analgesic drugs with fewer serious side effects than MOR agonists.

　The Upjohn company was first to report U-50488H (2)3 as a selective KOR agonist. Compound 2 produced analgesic effects without causing addiction as expected. Many researchers have since developed U-50488H derivatives. However, because the majority of KOR agonists (Upjohn type agonists) caused severe aversion and sedation, all of Upjohn type agonists were removed from early stage clinical trials.4 On the other hand, nalfurafine (3), a selective KOR agonist, showed analgesic and antipruritic effects without addiction and aversion, and was released as an antipruritic drug for kidney dialysis and hepatic disease patients with intolerable itch in Japan.5 Since the release of 3, many researchers have questioned why only 3 could separate the side effects.

　To elucidate the mechanism of attenuation of the aversive effect, Nagase and coworkers have been studying the active conformation of 3 for KOR.6 Recently, the docking study of 3 and KOR was conducted.7 The resulting binding mode of 3 is shown in Figure 2. Because of the hydrogen bond between the 14-hydroxy group and the 6-amide chain in 3, the 6-amide chain in 3 was proposed to be located on the upper side of the C-ring. The 6-amide chain would occupy the appropriate KOR binding pocket on the upper side of the C-ring, resulting in high KOR affinity. Based on this active conformation of 3 for KOR, in which the 6-amide chain would orient toward the upper side of the C-ring, Nagase and co-workers developed the selective KOR agonists, and these compounds showed an analgesic effect.6 However, in these studies, the mechanism of attenuation of the aversive effect in 3 remains unclear.

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