Aerobic oxidation of indolomorphinan without the 4,5-epoxy bridge and subsequent rearrangement of the oxidation product to spiroindolinonyl-C-normorphinan derivative.
Aerobic oxidation of indolomorphinan 1 without a 4,5-epoxy bridge proceeded in the presence of platinum catalyst to give indoleninomorphinan 2 or quinolono-C-normorphinan 5. The 4-hydroxy group would play an important role in deciding the course of the reaction. Treatment of 2a with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave spiroindolinonyl-C-normorphinan 3a whose structure resembles that of delta opioid receptor agonist spiroindanyloxymorphone (SIOM). Boron trichloride was effective for the reverse reaction from 3a to 2a without side reaction. This practical interconversion method between hydroxyindolenine and spiroindolinone would be useful for the design and construction of drug-like compound libraries. Although the compound 3b was expected to show the selectivity for delta opioid receptor because of the structural resemblance to SIOM, it was rather selective for 1 opioid receptor (1: K(i)=0.75nM; delta: K(i)=2.90nM; kappa: K(i)=13.4nM). The result suggests that the slight difference of the spatial location of the benzene rings in these compounds may definitively affect the binding affinity for delta opioid receptor.
Fujii
Hideaki
H
Kitasato University, Shirokane, Minato-ku, Tokyo, Japan.
Ogawa
Ryo
R
Ohata
Kenji
K
Nemoto
Toru
T
Nakajima
Mayumi
M
Hasebe
Ko
K
Mochizuki
Hidenori
H
Nagase
Hiroshi
H
D002384:Catalysis; D003164:Competitive Bidding; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
D009019:Morphinans; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D010984:Platinum