Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol
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Published:2023-10-03
Issue:19
Volume:28
Page:6925
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ISSN:1420-3049
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Container-title:Molecules
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language:en
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Short-container-title:Molecules
Author:
Karaki Fumika12, Takamori Taro1, Kawakami Koumei1, Sakurai Sae1, Hidaka Kyoko1, Ishii Kei1, Oki Tomoya1, Sato Noriko3, Atsumi Nao14, Ashizawa Karin14, Taguchi Ai14, Ura Asuka14, Naruse Toko1, Hirayama Shigeto12ORCID, Nonaka Miki4ORCID, Miyano Kanako4, Uezono Yasuhito4, Fujii Hideaki12ORCID
Affiliation:
1. Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan 2. Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan 3. Analytical Unit for Organic Chemistry, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan 4. Department of Pain Control Research, Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan
Abstract
In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKeyTM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the “hit” compounds for the µ and the δ receptors were totally inactive after purifications, three of the four “hits” for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins.
Funder
JSPS KAKENHI Kitasato University Research Grant for Young Researchers
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
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