Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure
- Hideaki Fujii ,
- Kohei Hayashida ,
- Akiyoshi Saitoh ,
- Akinobu Yokoyama ,
- Shigeto Hirayama ,
- Takashi Iwai ,
- Eriko Nakata ,
- Toru Nemoto ,
- Yuka Sudo ,
- Yasuhito Uezono ,
- Mitsuhiko Yamada , and
- Hiroshi Nagase
View Author Information
† School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
‡ Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan
§ Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Tokyo 104-0045, Japan
∥ Faculty of Pharmaceutical Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 274-8510, Japan
⊥ Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22 Hikokawado, Misato, Saitama 341-0005, Japan
*(H.F.) E-mail: [email protected]
Abstract
We synthesized compounds 4a,c–f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c–f,h,i exhibited full agonistic activities for the δ opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays. Subcutaneous administration of 4c produced dose-dependent and NTI (selective DOR antagonist)-reversible antinociception lacking any convulsive behaviors in the mice acetic acid writhing tests. The N-methyl derivative 4c is expected to be a promising lead compound for selective DOR agonists with a novel chemotype.
KEYWORDS:
Cited By
This article is cited by 6 publications.
- Eika Higashi, Shigeto Hirayama, Jun Nikaido, Marie Shibasaki, Tomomi Kono, Ayaka Honjo, Hiroko Ikeda, Junzo Kamei, Hideaki Fujii. Development of Novel δ Opioid Receptor Inverse Agonists without a Basic Nitrogen Atom and Their Antitussive Effects in Mice. ACS Chemical Neuroscience 2019, 10 (9) , 3939-3945. https://doi.org/10.1021/acschemneuro.9b00368
- Clémence Dupré, Olivier Bruno, Anne Bonnaud, Adeline Giganti, Olivier Nosjean, Céline Legros, Jean A. Boutin. Assessments of cellular melatonin receptor signaling pathways: β-arrestin recruitment, receptor internalization, and impedance variations. European Journal of Pharmacology 2018, 818 , 534-544. https://doi.org/10.1016/j.ejphar.2017.11.022
- Yoshikazu Watanabe, Kohei Hayashida, Daisuke Saito, Toshihiro Takahashi, Junichi Sakai, Eriko Nakata, Takashi Kanda, Takashi Iwai, Shigeto Hirayama, Hideaki Fujii, Tomio Yamakawa, Hiroshi Nagase. Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration. Bioorganic & Medicinal Chemistry Letters 2017, 27 (15) , 3495-3498. https://doi.org/10.1016/j.bmcl.2017.05.072
- Jean Boutin, Anne Bonnaud, Chantal Brasseur, Olivier Bruno, Nolwenn Lepretre, Peter Oosting, Sophie Coumailleau, Philippe Delagrange, Olivier Nosjean, Céline Legros. New MT2 Melatonin Receptor-Selective Ligands: Agonists and Partial Agonists. International Journal of Molecular Sciences 2017, 18 (7) , 1347. https://doi.org/10.3390/ijms18071347
- Kohei Hayashida, Shigeto Hirayama, Takashi Iwai, Yoshikazu Watanabe, Toshihiro Takahashi, Junichi Sakai, Eriko Nakata, Tomio Yamakawa, Hideaki Fujii, Hiroshi Nagase. Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities. Bioorganic & Medicinal Chemistry Letters 2017, 27 (12) , 2742-2745. https://doi.org/10.1016/j.bmcl.2017.04.059
- Giovanni Loriga, Paolo Lazzari, Ilaria Manca, Stefania Ruiu, Matteo Falzoi, Gabriele Murineddu, Mirko Emilio Heiner Bottazzi, Giovanni Pinna, Gérard Aimè Pinna. Novel diazabicycloalkane delta opioid agonists. Bioorganic & Medicinal Chemistry 2015, 23 (17) , 5527-5538. https://doi.org/10.1016/j.bmc.2015.07.036