Inhibition of nNOS activity in rat brain by synthetic kynurenines: structure-activity dependence.
The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process participating in neurodegeneration that characterizes some neurological disorders and acute cerebral insults. In looking for compounds with neuroprotective properties, a series of kynurenine derivatives were synthesized, and their effects on both the NMDA and nNOS activity in rat striatum were evaluated. Two compounds, 15a (2-acetamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) and 15c (2-butyramido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid), displayed more potent activities than the other synthetic compounds tested for the inhibition of NMDA excitability and nNOS activity. Two other compounds, 18a (2-acetamido-4-(3-methoxyphenyl)-4-oxobutyric acid) and 18c (2-butyramido-4-(3-methoxyphenyl)-4-oxobutyric acid), that have the same structure as 15a and 15c, except the amino group in R(1), showed different effects. Whereas compound 18a showed lower electrophysiological potency than compounds 15a and 15c in the inhibition of the NMDA-dependent excitability, compound 18c showed the opposite effect. Moreover, compounds 18a and 18c were unable to modify nNOS activity. The remaining kynurenines tested behave like compound 18a. These results suggest that a structure-related activity of these synthetic kynurenines and a N-H bond in a specific direction is necessary for some kynurenine analogues to inhibit nNOS activity.
Camacho
Encarnación
E
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Granada, Spain.
León
Josefa
J
Carrión
Adoración
A
Entrena
Antonio
A
Escames
Germaine
G
Khaldy
Huda
H
Acuña-Castroviejo
Darío
D
Gallo
Miguel A
MA
Espinosa
Antonio
A
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007737:Kynurenine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat