A new nitric oxide (NO) releaser: spontaneous NO release from FK409.
The remarkable vasorelaxant and anti-platelet effects of FK409 have been reported to be due to nitric oxide (NO) release. The purpose of the present study is to investigate the spontaneous NO-releasing pathway of FK409 in aqueous solutions. 1H-NMR spectra of FK409 suggested that the compound underwent a time-dependent elimination of the hydrogen atom at alpha-position of the nitro moiety (at the 5-position) in weakly alkaline solutions. In addition, the degradation of FK409 monitored by HPLC showed a pH-dependency accelerating with an increase of pH. These results revealed that the first step in the degradation of FK409 might be the hydroxyl ion-dependent subtraction of the hydrogen atom at the 5-position. On the other hand, NO release from FK409 also exhibited a pH-dependency, and the velocity of NO liberation was markedly enhanced above pH 6. Furthermore, a linear relationship between the rate of FK409 degradation and that of NO formation was observed, indicating that the rate-limiting step for NO formation is the same as that for degradation. Thus, the rate-limiting process of NO formation from FK409 is due to the deprotonation reaction of the hydrogen atom at the 5-position by hydroxyl ions. The deprotonation process appears to be an essential step for both FK409 degradation and NO release. On the basis of the results, a possible kinetic scheme for NO release from FK409 is proposed.
Fukuyama
S
S
Analytical Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kita
Y
Y
Hirasawa
Y
Y
Azuma
T
T
Sato
A
A
Morokoshi
N
N
Koda
S
S
Yasuda
T
T
Oka
S
S
Sakurai
H
H
D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D004578:Electron Spin Resonance Spectroscopy; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009569:Nitric Oxide / Q000032:analysis; D009573:Nitrites / Q000032:analysis; D009574:Nitro Compounds / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D013997:Time Factors; D014665:Vasodilator Agents / Q000737:chemistry*
D002021:Buffers; D009573:Nitrites; D009574:Nitro Compounds; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; C061872:FK 409