Novel delta opioid receptor agonists with oxazatricyclodecane structure

  • ACS Med Chem Lett. 2014 Jan 27;5(4):368-72. doi: 10.1021/ml400491k.
Hideaki Fujii  1 ,  Kohei Hayashida  1 ,  Akiyoshi Saitoh  2 ,  Akinobu Yokoyama  3 ,  Shigeto Hirayama  1 ,  Takashi Iwai  1 ,  Eriko Nakata  4 ,  Toru Nemoto  1 ,  Yuka Sudo  3 ,  Yasuhito Uezono  5 ,  Mitsuhiko Yamada  2 ,  Hiroshi Nagase  1
Affiliations
  • 1. School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
  • 2. Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry , 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan.
  • 3. 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.
  • 4. Discovery Research Laboratories, Nippon Chemiphar Co., Ltd. , 1-22 Hikokawado, Misato, Saitama 341-0005, Japan.
  • 5. Division of Cancer Pathophysiology, National Cancer Center Research Institute , 5-1-1 Tsukiji, Tokyo 104-0045, Japan.
PMID: 24900842 DOI: 10.1021/ml400491k
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
CellKey; DOR; Opioid; oxazatricyclodecane structure.