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Novel rearrangement reaction of morphinan derivatives and Design and synthesis of novel naphthalene-type orexin 2 receptor agonists

日野, 翼 筑波大学 DOI:10.15068/0002005512

2022.11.17

概要

A drug shows its pharmacological effect in binding to the specific target molecule called a receptor.1 The drug forms a complex with the receptor through intermolecular interactions such as hydrogen bonding, electrostatic interaction, and hydrophobic interaction, causing signaling to downstream tissues or effectors and resulting in the expression of the pharmaceutical effects. To develop a drug with a preferred pharmacological effect, a thorough understanding of the drug and its receptor is critical. In addition, the flexibility of drug molecules must be considered because a molecule with a highly flexible structure undergoes a loss of entropy when it binds to the receptor and forms a complex, resulting in weak activities and/or low bioavailability.

　The conformation of a drug showing a strong affinity with the receptor and the desired pharmacological effect is called the “active conformation”. The compound that adopts an active conformation consistently is less likely to cause side effects because it acts selectively on the target receptor and is thus more likely to be a promising drug molecule. Therefore, the synthetic approach to introducing conformational restriction to a molecule is a viable medicinal strategy to fix a structure into its active conformation.2 Indeed, this strategy has borne fruit in various drug discovery studies. Scheme 1 describes two typical examples.

　Compound 2 is restricted conformationally by the ring formation of Rivastigmine (1), an acetylcholinesterase inhibitor approved in 2000 for the treatment of Alzheimer’s disease, and it demonstrated 192-fold greater inhibitory activity than 1.3 In a related study, Kawasuji et al. developed a human immunodeficiency virus integrase inhibitor, dolutegravir (4) by introducing a ring skeleton into 3 aimed at fixing the pharmacophores into a specific configuration.4 Compound 4 demonstrated superior antiviral and pharmacokinetic profiles and is currently under clinical study (phase III). Inspired by these results, in this doctoral thesis, the author designed and synthesized molecules that mimic the active conformation by regulating the orientation of the side chain in flexible compounds. The goal of this research was to identify molecules that showed strong activities and high receptor selectivity, leading to the discovery of some promising drugs.

　In Chapter 2, a novel reaction on the morphinan skeleton is described. Morphine and other morphinan compounds have a strong analgesic effect and have been used as analgesics since ancient times. Many unusual reactions5 are known to be specific to the morphinan skeleton, which contains a reactive basic nitrogen atom and sequential chiral centers. In addition, the novel skeletons obtained from these reactions often exhibit interesting biological activities. Therefore, it is important to understand the reactivity of the morphinan skeleton not only for synthetic organic chemistry, but also in medicinal chemistry. To develop analgesic drugs with a morphinan skeleton, the author first targeted the opioid receptor classified in a G protein-coupled receptor (GPCR). The author has discovered a new reaction while synthesizing derivatives that mimicked the active conformation. The author obtained new derivatives that are expected to have fewer side effects.

　Chapter 3 describes the development of novel orexin receptor agonists based on the naphthalene skeleton. The term orexin is derived from the Greek word orexis, meaning appetite, and this neuropeptide exerts its physiological effects through the activation of orexin receptors classified as a GPCR. Orexin was initially studied as a neuropeptide that regulates feeding behavior because it is found in the feeding center and increases food intake when administered intracerebrally.6 Subsequently, the relationship between orexin and the sleep disorder, narcolepsy was revealed, and the role of orexin in the regulation of wakefulness and sleep has attracted much attention. While orexin antagonists have made remarkable progress in the treatment of insomnia today, studies on orexin agonists, which are expected to improve narcolepsy, have received limited attention. The author aimed to find novel naphthalene-type orexin 2 receptor (OX2R) agonists by conformational restriction of a diarylsulfonamide-type OX2R agonist with the postulated active conformation.

　Chapter 4 summarizes the conclusions of these studies.

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