Design and Synthesis of Pyrazolomorphinan Derivatives as Novel Delta Opioid Receptor Agonists

  • J Med Chem. 2025 Dec 25;68(24):25794-25808. doi: 10.1021/acs.jmedchem.5c02499.
Hideaki Fujii  1  2 ,  Chiharu Iwamatsu  1 ,  Saki Ishizaki  1 ,  Hideki Nakamura  3 ,  Daisuke Yamada  4 ,  Shuma Yamada  1 ,  Junichi Niwa  1 ,  Toshinori Yoshioka  4 ,  Pengfei Liu  4 ,  Shintaro Shirakura  4 ,  Fumika Karaki  1  2 ,  Shigeto Hirayama  1  2 ,  Akiyoshi Saitoh  4
Affiliations
  • 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. Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, Japan.
  • 4. Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
PMID: 41335044 DOI: 10.1021/acs.jmedchem.5c02499
Abstract

We designed pyrazolomorphinan derivatives 3 as novel δ Opioid Receptor (DOR) selective agonists with an unprecedented chemotype according to the drug design concept for the DOR selective agonist KNT-127 which encompassed the message-address concept, the accessory site concept, and the conversion of an indole ring into a quinoline ring. The designed compounds 3 as well as their regioisomers 9 showed potent DOR agonistic activities with low or almost no activities for the μ (MOR) and κ opioid receptors (KOR). Among the tested compounds, SYK-1106 (9j) bearing a cyclohexyl substituent was the most potent and efficacious DOR agonist (DOR: EC50 = 0.089 nM, Emax = 111%; agonistic activities for the MOR and KOR were not determined). SYK-1106 showed dose-dependent and DOR antagonist NTI reversible antidepressant-like effects at 0.3 mg/kg, s.c. in the mouse forced-swimming tests without an effect on locomotor activity and with no convulsive effects.

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