Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase.
Nitric oxide (NO.) is an important biomodulator of many physiological processes. The inhibition of inappropriate production of NO. by the isoforms of nitric oxide synthase (NOS) has been proposed as a therapeutic approach for the treatment of stroke, inflammation, and other processes. In this study, certain 2-nitroaryl-substituted amino acid analogues were discovered to inhibit NOS. Analogues bearing a 5-methyl substituent on the aromatic ring demonstrated maximal inhibitory potency. For two selected inhibitors, investigation of the kinetics of the enzyme showed the inhibition to be competitive with l-arginine. Additionally, functional NOS inhibition in tissue preparations was demonstrated.
Cowart
M
M
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Kowaluk
E A
EA
Daanen
J F
JF
Kohlhaas
K L
KL
Alexander
K M
KM
Wagenaar
F L
FL
Kerwin
J F
JF
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009574:Nitro Compounds; D009952:Ornithine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000109:Acetylcholine