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Drug-Target Interaction

Drug

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PubChem ID:4659569
Structure:
Synonyms:
(3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
(3,4-dihydroxy-5-nitrophenyl)-(4-methylphenyl)methanone
134308-13-7
3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone
3,4-dihydroxy-5'-methyl-5-nitrobenzophenone
AC-791
AC1NFJIT
BIDD:GT0032
C066340
C07949
C14H11NO5
CCRIS 7904
CHEBI:367825
CHEMBL1324
CPD-7664
D00786
DB00323
FT-0082597
HMS2089K14
I14-13303
LS-91226
Methanone, (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)-
Methanone,(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)
NCGC00181767-01
NCGC00181767-02
Ro 40-7592
Ro-40-7592
Roche brand of tolcapone
Tasmar
Tasmar (TN)
Tolcapone
Tolcapone (JAN/USAN/INN)
Tolcapone [USAN:INN]
UNII-CIF6334OLY
ATC-Codes:
Side-Effects:
Side-EffectFrequency
urinary tract infection0
sinusitis0
increased salivation0
seborrhea0
rhinitis0
pulmonary embolism0
pulmonary edema0
psychosis0
pruritus0
cerebrovascular accident0
syncope0
urinary incontinence0
upper respiratory tract infection0
tremor0
tooth disorder0
tinnitus0
thrombocytopenia0
tenosynovitis0
tachycardia0
polyuria0
pneumonia0
pharyngitis0
tumor0
nausea0
myocardial infarction0
fungal infection0
muscle cramps0
meningitis0
leukemia0
laryngitis0
nervousness0
neuralgia0
pericardial effusion0
paresthesia0
weakness0
palpitations0
pain0
ovarian cancer0
otitis media0
nocturia0
lacrimation disorder0
allergic reaction0
bradycardia0
blurred vision0
hypoxia0
thinking abnormal0
myalgia0
malaise0
sinus congestion0
gastric stasis0
neuropathy0
manic0
breast neoplasm0
mental deficiency0
cerebral ischemia0
sleep disorder0
increased sweating0
urinary frequency0
prostate cancer0
abnormal gait0
eye pain0
myocardial ischemia0
migraine0
dry mouth0
weight loss0
vomiting0
viral infection0
viral hepatitis0
vertigo0
vaginitis0
uterine hemorrhage0
urinary retention0
choreoathetosis0
mouth ulceration0
cataract0
peripheral edema0
emotional lability0
apathy0
agitation0
chills0
encephalopathy0
urticaria0
somnolence0
coronary artery disease0
constipation0
confusion0
colitis0
cholelithiasis0
cholecystitis0
chest pain0
neck pain0
cough0
decreased libido0
dizziness0
diplopia0
diarrhea0
diabetes mellitus0
delusions0
delirium0
dehydration0
dysphagia0
cerebral hemorrhage0
cellulitis0
carcinoma0
aortic stenosis0
anxiety0
anorexia0
angina pectoris0
anemia0
amnesia0
alopecia0
abscess0
apnea0
arrhythmia0
bronchitis0
bacterial infections0
atrial fibrillation0
asthma0
asthenia0
arthritis0
arthralgia0
arteriosclerosis0
abdominal pain0
kidney calculus0
herpes simplex0
hernia0
hemorrhage0
hemiplegia0
hematuria0
heart failure0
cardiac arrest0
headache0
herpes zoster0
hiccup0
arthrosis0
irritability0
influenza0
infection0
impotence0
hypotension0
hypertension0
hypercholesterolemia0
hallucinations0
glaucoma0
gastrointestinal hemorrhage0
epistaxis0
edema0
eczema0
ear pain0
dysuria0
dyspnea0
dyspepsia0
dyskinesia0
erythema multiforme0
esophagitis0
gastroenteritis0
furunculosis0
flatulence0
flank pain0
fever0
fatigue0
rash0
euphoria0
duodenal ulcer0

Target

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Uniprot ID:COMT_RAT
Synonyms:
Catechol O-methyltransferase
EC-Numbers:2.1.1.6
Organism:Rat
Rattus norvegicus
PDB IDs:1H1D 1JR4 1VID 2CL5 2ZLB 2ZTH 2ZVJ
Structure:
2ZVJ

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----
----
--2.2-
--930-
--2200-
--927000.0-

References:

11318939
D1-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors.. M A Vieira-Coelho; P Gomes; M P Serrão; P Soares-da-Silva (2001) Kidney international display abstract
BACKGROUND: In recent years, several nitrocatechol derivatives (tolcapone, entacapone, and nitecapone) have been developed and found to be highly selective and potent inhibitors of catechol-O-methyltransferase (COMT). More recently, natriuretic properties were described for two of these compounds (entacapone and nitecapone), although this was not accompanied by enhanced urinary excretion of dopamine. We hypothesized that nitrocatechol derivatives stimulate D1-like dopamine receptors. METHODS: Adult male Wistar rats were treated with a nitrocatechol COMT inhibitor (entacapone, tolcapone, or nitecapone, 30 mg/kg, orally), and the urinary excretion of dopamine and sodium was quantitated. The interaction of nitrocatechol derivatives with D1-like receptors was evaluated by their ability to displace [3H]-Sch23390 binding from membranes of rat renal cortex and cAMP production in opossum kidney (OK) cells. RESULTS: Urinary excretion of sodium (micromol/h) was markedly increased by all three nitrocatechol derivatives: vehicle, 55.0 +/- 5.6; entacapone, 98.4 +/- 9.3; tolcapone, 97.5 +/- 9.3; and nitecapone, 120.5 +/- 12.6. Pretreatment with the selective D1 antagonist Sch 23390 (60 microg/kg) completely prevented their natriuretic effects. Nitecapone and tolcapone were equipotent (IC50s of 48 and 42 micromol/L) and more potent than entacapone and dopamine (IC50s of 107 and 279 micromol/L) in displacing [3H]-Sch23390 binding. In OK cells, all three nitrocatechol derivatives significantly increased cAMP accumulation and reduced Na(+)/H(+) exchange and Na(+),K(+)-ATPase activities, this being prevented by a blockade of D1-like receptors. CONCLUSION: Stimulation of D1-like dopamine receptors and inhibition of Na(+)/H(+) exchange and Na(+),K(+)-ATPase activities by nitrocatechol COMT inhibitors may contribute to natriuresis produced by these compounds.
11489299
Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.. M Huotari; M Passlin; H L Nordberg; M Forsberg; S Kotisaari; L Tuomisto; F Shintani; K F Tanaka; I Reenilä; K Laitinen; P T Männistö (2001) Journal of neuroscience methods display abstract
6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.
12111468
Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.. M Gerlach; W Ukai; H Ozawa; P Riederer (2002) Journal of neural transmission (Vienna, Austria : 1996) display abstract
Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.