Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands

• Published in: Bioorganic & medicinal chemistry letters 2022-01, Vol.56, p.128485-128485, Article 128485
• Main Authors: Iio, Keita, Kutsumura, Noriki, Nagumo, Yasuyuki, Saitoh, Tsuyoshi, Tokuda, Akihisa, Hashimoto, Kao, Yamamoto, Naoshi, Kise, Ryoji, Inoue, Asuka, Mizoguchi, Hirokazu, Nagase, Hiroshi
• Format: Article
• Language: English
• Subjects: Agonist; Animals; Behavior, Animal - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Mice; Molecular Structure; Morphinan; Morphinans - adverse effects; Morphinans - chemical synthesis; Morphinans - chemistry; Mrgprb2; MRGPRX2; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - metabolism; Opioid; Pruritus - chemically induced; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Receptors, Neuropeptide - antagonists & inhibitors; Receptors, Neuropeptide - metabolism; Receptors, Opioid, delta; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128485

[Display omitted] Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (–)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1 also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2a by a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2a activated both human MRGPRX2 and the mouse orthologue Mrgprb2 in in vitro experiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2a serves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.