Synthesis of phosphorus-containing amino acid analogs as inhibitors of nitric oxide synthase

Nitric oxide is known to function as a neurotransmitter in the central nervous system. It is also known to be involved in the control nervous system excitatory amino acid neurotransmission cascade. Activation of excitatory amino acid receptors causes an influx of calcium, which activates nitric oxide synthase. The resulting increase in intracellular nitric oxide activates soluble guanylate cyclase, leading to a rise in cyclic guanosine monophosphate. The excitatory amino acids giutamate and aspartate are found in the vestibular system and have been postulated to function as vestibular system neurotransmitters. Although nitric oxide has ben investigated as a neurotransmitter in other tissues, no published studies have examined the role of nitric oxide in the vestibular system. Neuronal NADPH-dlaphorase has been characterized as a nitric oxide synthase. This enzyme catalyzes the conversion of L-arginine to l-citrulline, producing nitric oxide during the reaction. We used a histochemical stain characterized by Hope et al. (Proc Natl Acad Sci 1991;88:2811) as specific for neuronal nitric oxide synthase to localize the enzyme in the rat vestibular system. An Immunocytochemical stain was used to examine rat Inner ear tissue for the presence of the enzyme's end product, l-citrulline, thereby demonstrating nitric oxide synthase activity. Staining of vestibular ganglion sections showed nitric oxide synthase presence and activity in ganglion cells and nerve fibers. These results Indicate the presence of active nitric oxide synthase in these tissues and suggest modulation of vestibular neurotransmission by nitric oxide.

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Uptake of nitric oxide synthase inhibitors by macrophage RAW 264.7 cells

Biochemical Journal ◽

10.1042/bj3010313 ◽

1994 ◽

Vol 301 (2) ◽

pp. 313-316 ◽

Cited By ~ 32

Author(s):

K Schmidt ◽

P Klatt ◽

B Mayer

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Nitric Oxide Synthase ◽

Amino Acid Transporter ◽

Raw 264.7 Cells ◽

Cationic Amino Acid ◽

Nitric Oxide Synthase Inhibitors ◽

System L ◽

Acid Transporter ◽

Oxide Synthase

Uptake of the nitric oxide synthase inhibitors NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA) by macrophages is mediated by two different mechanisms. Activation of the cells with cytokines resulted in an up-regulation of L-NMA uptake but did not affect L-NNA transport. Characterization of the transport sites revealed that uptake of L-NMA is mediated by a cationic amino acid transporter (system y+) whereas a neutral amino acid transporter (system L) accounts for the uptake of L-NNA.

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Effects of sesquiterpenes and amino acid–sesquiterpene conjugates from the roots of Saussurea lappa on inducible nitric oxide synthase and heat shock protein in lipopolysaccharide-activated macrophages

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(02)00471-6 ◽

2003 ◽

Vol 11 (5) ◽

pp. 709-715 ◽

Cited By ~ 64

Author(s):

Hisashi Matsuda ◽

Iwao Toguchida ◽

Kiyofumi Ninomiya ◽

Tadashi Kageura ◽

Toshio Morikawa ◽

...

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Heat Shock ◽

Nitric Oxide Synthase ◽

Heat Shock Protein ◽

Inducible Nitric Oxide Synthase ◽

Activated Macrophages ◽

Saussurea Lappa ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Preliminary evaluation of PARACEST MRI agents for the detection of nitric oxide synthase

Canadian Journal of Chemistry ◽

10.1139/cjc-2016-0179 ◽

2016 ◽

Vol 94 (8) ◽

pp. 715-722 ◽

Cited By ~ 2

Author(s):

Mojmír Suchý ◽

Alex X. Li ◽

Yin Liu ◽

Qingping Feng ◽

Robert Bartha ◽

...

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Nitric Oxide Synthase ◽

Chemical Exchange ◽

Acid Amide ◽

Chemical Exchange Saturation Transfer ◽

Preliminary Evaluation ◽

Resonance Imaging ◽

Terminal Amino ◽

Oxide Synthase

Several paramagnetic chemical exchange saturation transfer magnetic resonance imaging (PARACEST MRI) agents for the potential detection of nitric oxide synthase (NOS) have been synthesized and evaluated. These agents are based on an amino acid- or dipeptide-decorated DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide) chelator possessing either Tm3+ or Dy3+. The amino acid and dipeptide decorated DOTAMs were designed such that the terminal amino acid pendant group was l-arginine, which may be converted to l-citrulline by NOS. Preliminary evaluation has revealed that some of the l-arginine-decorated complexes are recognized and metabolized by the NOS. Differences in the CEST properties between Dy3+-metallated l-arginine- and l-citrulline-modified complexes suggest that these might be suitable for imaging of the NOS enzymatic activity.

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