Oudenone, a novel tyrosine hydroxylase inhibitor from microbial origin

Ono, Masaji; Okamoto, Masaru; Kawabe, Norio; Umezawa, Hamao; Takeuchi, Tomio; Iinuma, Hisae; Takahashi, Shuji

doi:10.1021/ja00734a054

Cited by 29 publications

(10 citation statements)

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“…Metyrosine is, however, rarely used for such treatment as it can cause depression [14], but remains valuable in treating pheochromocytoma and also resistant hypertension [12–14]. Oudenone [17] and aquayamycin are further classical inhibitors of TH [18], but are structurally unrelated to catecholamines and demonstrate that structurally diverse compounds can interact with TH. In the present study, PPCA (ΔG, −6.95 kcal/mol; K i , 8 μM) displayed a binding interaction with human TH comparable to the original TH substrate, L-Tyrosine (ΔG, −5.96 kcal/mol; K i , 42.74 μM).…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking Study of Catecholamines and [4-(Propan-2-yl) Phenyl]Carbamic acid with Tyrosine Hydroxylase

Parveen¹,

Nawaz²,

Shakil³

et al. 2012

CNSNDDT

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Parkinson’s disease is a major age-related neurodegenerative disorder. As the classical disease-related motor symptoms are associated with the loss of dopamine-generating cells within the substantia nigra, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines has become an important target in the development of Parkinson’s disease drug candidates, with the focus to augment TH levels or its activity. By contrast, TH inhibitors are of relevance in the treatment of conditions associated with catecholamine over-production, as occurs in pheochromocytomas. To aid characterizing new drug candidates, a molecular docking study of catecholamines and a novel hypothetical compound [4-(propan-2-yl) phenyl]carbamic acid (PPCA) with TH is described. Docking was performed using Autodock4.2 and results were analyzed using Chimera1.5.2. All the studied ligands were found to bind within a deep narrow groove lined with polar aromatic and acidic residues within TH. Our results corroborated a ‘hexa interacting amino acids unit’ located in this deep narrow groove crucial to the interaction of PPCA and the studied catecholamines with TH, whereby the ‘His361-His336 dyad’ was found to be even more crucial to these binding interactions. PPCA displayed a binding interaction with human TH that was comparable to the original TH substrate, L-tyrosine. Hence PPCA may warrant in vitro and in vivo characterization with TH to assess its potential as a candidate therapeutic.

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Section: Resultsmentioning

confidence: 99%

Molecular Docking Study of Catecholamines and [4-(Propan-2-yl) Phenyl]Carbamic acid with Tyrosine Hydroxylase

Parveen¹,

Nawaz²,

Shakil³

et al. 2012

CNSNDDT

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“…Recently, several new inhibitors of tyrosine hydroxylase and dopamine-i3 hydroxylase from microbial origin have been discovered (3)(4)(5)(6)(7)(8)(9)(10). Oudenone is one of these microbial inhibitors of tyrosine hydroxylase.…”

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confidence: 99%

“…The purpose of the present work was to investigate the pharmacological actions of oudenone (synthetized according to the procedure by Ohno et al (4)) in detail and to elucidate the mechanisms whereby these actions were caused by oudenone.…”

mentioning

confidence: 99%

Pharmacodynamic Actions of (S)-2-[4, 5-Dihydro5-Propyl-2 (3h)-Furylidene]-1, 3-Cyclopentanedione (Oudenone)

Ozawa

Koide

1976

Jpn.J.Pharmacol

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Abstract-The pharmacodynamic actions of (S)-2-[4,5-dihydro-5-propyl-2(3H)-furyli dene]-l,3-cyclopentanedione (oudenone) were studied in both anesthetized animals and isolated organs. Oudenone (10-40 mg/kg i.v.) induced an initial rise in blood pressure followed by a prolonged hypotension in the anesthetized rats. In unanesthetized spontaneously hypertensive rats (SHR), oudenone (5-200 mg/kg p.o.) caused a dose related decrease in the systolic blood pressure. The initial pressor effect was dimi nished by pretreatments with phentolamine, guanethidine, hexamethonium and was abolished in the pithed rats. In addition, intracisternal administrations of oudenone (100-600 ,!g;'kg) showed a marked increase in blood pressure in the anesthetized rats, suggesting that the pressor effect may be due to centrally mediated actions. Oudenone, given intra-arterially into the femoral artery (400-800 pg/kg), caused a long-lasting vasodilation in anesthetized dogs. At a relatively high dose (40 mg/kg i.v.), oudenone antagonized all pressor responses to autonomic agents and central vagus nerve stimu lation in anesthetized rats and dogs, however, oudenone showed no anti-cholinergic, histaminergic, beta-adrenergic and adrenergic neuron blocking properties.Tyrosine hydroxylase, which catalyzes the hydroxylation of tyrosine to form dihy droxyphenylalanine, is the rate limiting step in the catecholamine biosynthesis (1) and many substances have been tested as potential inhibitions of this enzyme (2). Recently, several new inhibitors of tyrosine hydroxylase and dopamine-i3 hydroxylase from microbial origin have been discovered (3-10). Oudenone is one of these microbial inhibitors of tyrosine hydroxylase.From biochemical experiments, oudenone has been reported to inhibit tyrosine hydroxyl ase both in vitro and in vivo and decreases endogenous catecholamine levels (3, 5), however, pharmacological actions of oudenone have yet to be clarified. The purpose of the present work was to investigate the pharmacological actions of oudenone (synthetized according to the procedure by Ohno et al. (4)) in detail and to elucidate the mechanisms whereby these actions were caused by oudenone. MATERIALS AND METHODS Experiments in the anesthetized normotensive ratsMale Wistar rats weighing 280-350 g were anesthetized with urethane (1.5 g/kg s.c.), the trachea cannulated and arterial blood pressure and heart rate were recorded from the right common carotid artery with a pressure transducer (Nihon Kohden, MPU-0.5) con

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“…Specific and potent inhibitors of the enzymes involved in catecholamine biosynthesis have been recently discovered from the culture media of microorganisms by Umezawa et al (7,11,12,13,17). Oudenone ( (S)-2-[4, 5-dihydro-5-propyl-2 (3H)-furylidene]-1, 3-cyclopentanedione) (12, 13,17) is an inhibitor of tyrosine hydroxylase which was isolated from the culture filtrate of Oudenansiella radieata and shown to inhibit the enzyme in vivo to reduce the endogenous level of catecholamines.…”

mentioning

confidence: 99%

“…Oudenone ( (S)-2-[4, 5-dihydro-5-propyl-2 (3H)-furylidene]-1, 3-cyclopentanedione) (12, 13,17) is an inhibitor of tyrosine hydroxylase which was isolated from the culture filtrate of Oudenansiella radieata and shown to inhibit the enzyme in vivo to reduce the endogenous level of catecholamines. Fusaric acid (5-butylpicolinic acid) is an inhibtor of dopamine-,3-hydroxylase which was isolated from the culture filtrate of a fungus of Fusarium species and shown to be a potent inhibitor of the enzyme in vitro and in vivo (7, 11).…”

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confidence: 99%

Effects of Inhibitors of Catecholamine-Synthesizing Enzymes on the Mouse Adrenal Medulla

Nagatsu

Sotokawa

Sano

1972

Acta Histochem. Cytochem

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Oudenone, a novel tyrosine hydroxylase inhibitor from microbial origin

Cited by 29 publications

References 0 publications

Molecular Docking Study of Catecholamines and [4-(Propan-2-yl) Phenyl]Carbamic acid with Tyrosine Hydroxylase

Molecular Docking Study of Catecholamines and [4-(Propan-2-yl) Phenyl]Carbamic acid with Tyrosine Hydroxylase

Pharmacodynamic Actions of (S)-2-[4, 5-Dihydro5-Propyl-2 (3h)-Furylidene]-1, 3-Cyclopentanedione (Oudenone)

Effects of Inhibitors of Catecholamine-Synthesizing Enzymes on the Mouse Adrenal Medulla

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