Effects of arginine derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells.
The effects of L-arginine (Arg) derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells were examined. The Arg derivatives were modified at the -NH2, -COOH, C alpha-proton or guanidino group of Arg. Among the synthesized derivatives, eight compounds, i.e. the 5-(dimethylamino)-1-naphthalenesulfonyl (DNS) ones, especially N-cyclohexyl-2-(N-DNSamino)-5-guanidino-2-methylvaleramide and 1-[2-(N-DNSamino)-2-(2-imino-1,2,3,4,5,6-hexahydropyrimidin- 4-yl)acetyl]- piperidine, were found to inhibit the activity of crude guanylate cyclase in the 105,000 g supernatant fraction of the cell homogenate. The enzyme, partially purified by a column of Chelex 100 Na+, was also inhibited by these eight compounds. The mode of the inhibition was competitive. The Ki values were in the range of 2-8 microM for the enzyme in the 105,000 g supernatant fraction and 3-16 microM for the partially purified enzyme, in the presence of Mg2+ as a metal cofactor. In contrast, a new derivative, methyl 2-amino-5-guanidinovalerate (M Arg ME), as well as the Arg methyl ester (Arg ME) and Arg; were found to enhance the activity of the partially purified guanylate cyclase; KA values of M Arg ME, Arg ME and Arg were approximately 9, 4 and 3 microM respectively. From these results, the free guanidino group including 2-imino-1,2,3,4,5,6-hexahydropyrimidin-4-yl or 2-imino-1,2,3,4,5,6-hexahydropyrimidin-5-yl and modification of the --NH2 residue with a hydrophobic group such as DNS seemed to be essential for inhibition of the guanylate cyclase; however, the guanidino and --NH2 residue of Arg should be free for activation by these Arg derivatives.
Yoshioka
M
M
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Fujimori
H
H
Deguchi
T
T
Masayasu
H
H
Suzuki
K
K
Inamura
K
K
Kosasayama
A
A
Ishikawa
F
F
D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001667:Binding, Competitive; D003619:Dansyl Compounds; D006160:Guanosine Triphosphate / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008274:Magnesium / Q000494:pharmacology; D015394:Molecular Structure; D009447:Neuroblastoma / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D003619:Dansyl Compounds; D006160:Guanosine Triphosphate; D001120:Arginine; D006162:Guanylate Cyclase; D008274:Magnesium