Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain

  • Bioorg Med Chem. 2015 Oct 1;23(19):6271-9. doi: 10.1016/j.bmc.2015.08.036.
Ryo Nakajima  1 ,  Naoshi Yamamoto  2 ,  Shigeto Hirayama  3 ,  Takashi Iwai  3 ,  Akiyoshi Saitoh  4 ,  Yasuyuki Nagumo  2 ,  Hideaki Fujii  3 ,  Hiroshi Nagase  5
Affiliations
  • 1. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
  • 2. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
  • 3. School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
  • 4. Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo 187-8553, Japan.
  • 5. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: [email protected].
PMID: 26346669 DOI: 10.1016/j.bmc.2015.08.036
Abstract

We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine.

Keywords
Analgesic; KOR selectivity; Nalfurafine; Opioid; Propellane.