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

Ryo Nakajima; Naoshi Yamamoto; Shigeto Hirayama; Takashi Iwai; Akiyoshi Saitoh; Yasuyuki Nagumo; Hideaki Fujii; Hiroshi Nagase

doi:10.1016/j.bmc.2015.08.036

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. Epub 2015 Aug 28.

Authors

Ryo Nakajima¹, Naoshi Yamamoto², Shigeto Hirayama³, Takashi Iwai³, Akiyoshi Saitoh⁴, Yasuyuki Nagumo², Hideaki Fujii³, Hiroshi Nagase⁵

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: nagase.hiroshi.gt@u.tsukuba.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemistry*
Analgesics, Opioid / chemical synthesis*
Analgesics, Opioid / metabolism
Analgesics, Opioid / therapeutic use
Animals
CHO Cells
Cricetinae
Cricetulus
Guinea Pigs
Male
Mice
Mice, Inbred ICR
Morphinans / chemical synthesis*
Morphinans / chemistry
Morphinans / metabolism
Morphinans / therapeutic use
Pain / chemically induced
Pain / drug therapy
Protein Binding
Receptors, Opioid, kappa / agonists
Receptors, Opioid, kappa / metabolism
Receptors, Opioid, mu / agonists
Receptors, Opioid, mu / metabolism
Spiro Compounds / chemical synthesis*
Spiro Compounds / chemistry
Spiro Compounds / metabolism
Spiro Compounds / therapeutic use
Structure-Activity Relationship

Substances

Amides
Analgesics, Opioid
Morphinans
Receptors, Opioid, kappa
Receptors, Opioid, mu
Spiro Compounds
YNT-854
TRK 820