title: Nitroaromatic amino acids as inhibitors of neuronal nitric oxide synthase.
abstract: 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.
authors.affiliation: Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cowart
authors.forename: E A
authors.initials: EA
authors.lastname: Kowaluk
authors.forename: J F
authors.initials: JF
authors.lastname: Daanen
authors.forename: K L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: K M
authors.initials: KM
authors.lastname: Alexander
authors.forename: F L
authors.initials: FL
authors.lastname: Wagenaar
authors.forename: J F
authors.initials: JF
authors.lastname: Kerwin
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009574:Nitro Compounds; D009952:Ornithine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000109:Acetylcholine