Suppression of respiratory burst in human neutrophils by new synthetic pyrrolo-benzylisoquinolines.
Reactive oxygen species produced by neutrophils contribute to the pathogenesis of inflammatory diseases. In this study, the inhibition of superoxide anion (O2*-) generation in human neutrophils by new synthetic pyrrolo-benzylisoquinoline derivatives was determined. We found that KW-2, KW-5, and KW-7 (8,9-dimethoxyl-1-(R-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-2,3-dione; where R is 3-chloro, 3-bromo, and 4-methoxy, respectively) were the most effective inhibitors of formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced O2*- release in human neutrophils. KW-2, KW-5, and KW-7 displayed no antioxidant or O2*--scavenging ability. The inhibition of O2*- generation was reversed by the protein kinase (PK)A inhibitor, N-(2-((p-bromocinnamyl)amino)ethyl)-5-isoquinolinesulfonamide (H89), but not by the PKG inhibitor (8R,9S,11S)-(-)-2-methyl-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta(cde)trinen-1-one (KT5823), or the soluble guanylate cyclase (sGC) inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). KW derivatives increased cellular cyclic AMP concentrations through the inhibition of phosphodiesterase (PDE) activity but not the elevation of adenylate cyclase (AC) activity. These results indicate that inhibition of FMLP-induced respiratory burst in human neutrophils by KW derivatives are cyclic AMP/PKA-dependent and are due to inhibition of PDE. The new chemical skeleton of PDE inhibitors may protect against the progression of inflammation.
Hwang
Tsong-Long
TL
Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan. htl@mail.cgu.edu.tw
Wu
Yang-Chang
YC
Yeh
Shang-Hsin
SH
Kuo
Reen-Yen
RY
D000293:Adolescent; D000328:Adult; D044182:Benzylisoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D016897:Respiratory Burst / Q000187:drug effects* / Q000502:physiology
D044182:Benzylisoquinolines; D011758:Pyrroles