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Drug-Target Interaction

Drug

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PubChem ID:1125
Structure:
Synonyms:
(1R,2S)-(2-Amino-3,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)-1,2-propandiol
(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-1H-pteridin-4-one
(6R)-2-amino-6-[(1S,2R)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-1H-pteridin-4-one
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin
17528-72-2
2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydoro-4(1H)-pteridinone
2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one
2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydropteridin-4(3H)-one
4(1H)-Pteridinone, 5,6,7,8-tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-
5,6,7,8 Tetrahydrobiopterin
5,6,7,8-erythro-tetrahydrobiopterin
5,6,7,8-tetra-H-biopterin
5,6,7,8-Tetrahydro-2-amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone
5,6,7,8-tetrahydro-L-erythrobiopterin
5,6,7,8-tetrahydrobiopterin
5,6,7,8-tetrahydrodictyopterin
5-26-18-00418 (Beilstein Handbook Reference)
6R-BH4
6R-L-erythro-5,6,7,8-tetrahydrobiopterin
6s-5,6,7,8-Tetrahydrobiopterin
7-tetrahydrobiopterin
BH4
BPH4
BRN 0544742
C00272
C9H15N5O3
CHEBI:15372
DB00360
DB02692
DB03918
Kuvan
L-erythro-2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3H)-pteridi
L-erythro-2-Amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3H)-pteridinon
LS-126327
Phenoptin
phenylalanine hydroxylase cofactor
TETRA-H-BIOPTERIN
tetra-hydro-biopterin
tetrahydro-6-biopterin
tetrahydrobiopterin
THBP
Side-Effects:
Side-EffectFrequency
convulsions0.0010
testicular carcinoma0
rhinorrhea0
diarrhea0
vomiting0
peripheral edema0
gastrointestinal hemorrhage0
pain0
nausea0
arthralgia0
upper respiratory tract infection0
streptococcal infections0
headache0
abdominal pain0
dizziness0
gastritis0
rash0
agitation0
respiratory failure0
fever0
nasal congestion0
myocardial infarction0
cough0
hemorrhage0
urinary tract infection0
neutropenia0
polyuria0
irritability0

Target

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Uniprot ID:Q62710_RAT
Synonyms:
Nitric oxide synthase
EC-Numbers:-
Organism:Rat
Rattus norvegicus
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----

References:

16738031
Tetrahydrobiopterin protects against guanabenz-mediated inhibition of neuronal nitric-oxide synthase in vitro and in vivo.. Anwar Y Dunbar; Gary J Jenkins; Suree Jianmongkol; Mikiya Nakatsuka; Ezra R Lowe; Miranda Lau; Yoichi Osawa (2006) Drug metabolism and disposition: the biological fate of chemicals display abstract
It is established that guanabenz inhibits neuronal nitric-oxide (NO) synthase (nNOS) and causes the enhanced proteasomal degradation of nNOS in vivo. Although the time- and NADPH-dependent inhibition of nNOS has been reported in studies where guanabenz was incubated with crude cytosolic preparations of nNOS, the exact mechanism for inhibition is not known. Moreover, even less is known about how the inhibition of nNOS triggers its proteasomal degradation. In the current study, we show, with the use of purified nNOS, that guanabenz treatment leads to the oxidation of tetrahydrobiopterin and formation of a pterin-depleted nNOS, which is not able to form NO. With the use of 14C-labeled guanabenz, we were unable to detect any guanabenz metabolites or guanabenz-nNOS adducts, indicating that reactive intermediates of guanabenz probably do not play a role in the inhibition. Superoxide dismutase, however, prevents the guanabenz-mediated oxidation of tetrahydrobiopterin and inhibition of nNOS, suggesting the role of superoxide as an intermediate. Studies in rats show that administration of tetrahydrobiopterin prevents the inhibition and loss of penile nNOS due to guanabenz, indicating that the loss of tetrahydrobiopterin plays a major role in the effects of guanabenz in vivo. Our findings are consistent with the destabilization and enhanced degradation of nNOS found after tetrahydrobiopterin depletion. These studies suggest that drug-mediated destabilization and subsequent enhanced degradation of protein targets will likely be an important toxicological consideration.
9920651
Blockade of tetrahydrobiopterin synthesis protects neurons after transient forebrain ischemia in rat: a novel role for the cofactor.. S Cho; B T Volpe; Y Bae; O Hwang; H J Choi; J Gal; L C Park; C K Chu; J Du; T H Joh (1999) The Journal of neuroscience : the official journal of the Society for Neuroscience display abstract
The generation of nitric oxide (NO) aggravates neuronal injury. (6R)-5,6,7,8-Tetrahydro-L-biopterin (BH4) is an essential cofactor in the synthesis of NO by nitric oxide synthase (NOS). We attempted to attenuate neuron degeneration by blocking the synthesis of the cofactor BH4 using N-acetyl-3-O-methyldopamine (NAMDA). In vitro data demonstrate that NAMDA inhibited GTP cyclohydrolase I, the rate-limiting enzyme for BH4 biosynthesis, and reduced nitrite accumulation, an oxidative metabolite of NO, without directly inhibiting NOS activity. Animals exposed to transient forebrain ischemia and treated with NAMDA demonstrated marked reductions in ischemia-induced BH4 levels, NADPH-diaphorase activity, and caspase-3 gene expression in the CA1 hippocampus. Moreover, delayed neuronal injury in the CA1 hippocampal region was significantly attenuated by NAMDA. For the first time, these data demonstrate that a cofactor, BH4, plays a significant role in the generation of ischemic neuronal death, and that blockade of BH4 biosynthesis may provide novel strategies for neuroprotection.