Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain.
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.
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
Ryo
R
Nakajima
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Naoshi
N
Yamamoto
School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Shigeto
S
Hirayama
School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Takashi
T
Iwai
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo 187-8553, Japan.
Akiyoshi
A
Saitoh
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Yasuyuki
Y
Nagumo
School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Hideaki
H
Fujii
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.
Hiroshi
H
Nagase
D000577:Amides / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000577:Amides; D000701:Analgesics, Opioid; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; C000608969:YNT-854; C111212:TRK 820
Analgesic; KOR selectivity; Nalfurafine; Opioid; Propellane