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Direct inhibition of tyrosine hydroxylase from PC-12 cells by catechol derivatives

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Summary

Several drugs with a catechol moiety were studied for their potency to inhibit tyrosine hydroxylase (TH) from PC-12 cells in vitro. When the natural compounds tested were compared, dopamine, norepinephrine and 2(3,4-dihydroxyphenyl)-ethanol (DOPET) were most effective (IC50 between 1.4 and 3.6 μM with 0.5 μM 6(R,S)-l-erythro-5,6,7,8-tetrahydrobiopterin as cofactor). 3,4-Dihydroxyphenylalanine (DOPA; IC50: 35 μM) and 3,4-dihydroxyphenylacetic acid (DOPAC; IC50: 180 μM were less potent inhibitors. Among the synthetic drugs possessing catechol moiety, isoproterenol, (±)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) and (±)-2-dimethylamino-6,7-dihydroxy-tetrahydronaphthalene (TL-99) had the same inhibitory effects as the natural catecholamines (IC50 between 1.6 and 3.9 μM), whereas the apomorphine derivatives and 2,3,4,5-tetrahydro-1-phenyl-1 H-3-benzazepine-7,8-diol (SKF 38393) were even more potent (IC50: 0.5–0.8 μM).

These results demonstrate that natural catechols and certain drugs (e.g. 6,7-ADTN, TL-99, SKF 38393) are more effective direct blockers of tyrosine hydroxylase than generally assumed provided appropriate assay conditions are used. In the case of dopamine and norepinephrine, these findings suggest a reevaluation of their role for feedback control of tyrosine hydroxylase in vivo.

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Abbreviations

6,7-ADTN:

(±)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene

BH4 :

6(R,S)-l-erythro-5,6,7,8-tetrahydrobiopterin

DMPH4 :

2-amino-4-hydroxy-6,7-dimethyl-tetrahydropteridine

DOPA:

3,4-dihydroxyphenylalanine

DOPAC:

3,4-dihydroxyphenylacetic acid

DOPET:

2(3,4-dihydroxyphenyl)ethanol

ELCD:

electrochemical detection

6-MPH4 :

6-methyl-5,6,7,8-tetrahydropteridine

NSD 1015:

3-hydroxy-benzyl-hydrazine

SKF 38393:

2,3,4,5-tetrahydro-1-phenyl-1 H-3-benzazepine-7,8-diol

TH:

tyrosine hydroxylase

TL-99:

(±)-2-dimethylamino-6,7-dihydroxy-tetrahydronaphthalene

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Authors and Affiliations

  1. Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69/73, D-1000, Berlin 33

    G. Laschinski, B. Kittner & M. Bräutigam

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  1. G. Laschinski
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  2. B. Kittner
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  3. M. Bräutigam
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Laschinski, G., Kittner, B. & Bräutigam, M. Direct inhibition of tyrosine hydroxylase from PC-12 cells by catechol derivatives. Naunyn-Schmiedeberg's Arch. Pharmacol. 332, 346–350 (1986). https://doi.org/10.1007/BF00500085

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  • DOI: https://doi.org/10.1007/BF00500085

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