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Drug-Target Interaction

Drug

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PubChem ID:44257
Structure:
Synonyms:
(-)-(6R)-2-Amino-6-((1R,2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3H)-
(-)-(6R)-2-Amino-6-((1R,2S)-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4(3H)-pteridinone
(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridin-4(1H)-one
(6R,1'R,2'S)-5,6,7,8 TETRAHYDROBIOPTERIN
17528-72-2
27070-47-9
5,6,7,8-TETRAHYDROBIOPTERIN
62989-33-7
6R-5,6,7,8-Tetrahydrobiopterin
6R-BH4
6R-L-5,6,7,8-Tetrahydrobiopterin
BCBcMAP01_000204
BH4
CHEBI:59560
H4B
Kuvan
R-THBP
Sapropterin
Sapropterin (INN)
SAPROPTERIN HYDROCHLORIDE
Sapropterin [INN]
Sapropterina
Sapropterina [INN-Spanish]
Sapropterinum
Sapropterinum [INN-Latin]
SMP1_000285
TETRAHYDROBIOPTERIN
THB
ZINC13585233
ATC-Codes:
Side-Effects:
Side-EffectFrequency
convulsions0.0010
abdominal pain0
neutropenia0
pain0
polyuria0
streptococcal infections0
upper respiratory tract infection0
urinary tract infection0
vomiting0
agitation0
peripheral edema0
testicular carcinoma0
respiratory failure0
nausea0
nasal congestion0
myocardial infarction0
arthralgia0
cough0
diarrhea0
dizziness0
rash0
fever0
gastritis0
gastrointestinal hemorrhage0
headache0
hemorrhage0
irritability0
rhinorrhea0

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.