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

Abstract

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 microM with 0.5 microM 6(R,S)-L-erythro-5,6,7,8-tetrahydrobiopterin as cofactor). 3,4-Dihydroxyphenylalanine (DOPA; IC50: 35 microM) and 3,4-dihydroxyphenylacetic acid (DOPAC; IC50: 180 microM 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 microM), 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 microM). 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.

Desensitization of α₂-Adrenoceptors which Regulate Noradrenaline Synthesis and Release after Chronic Treatment with Clorgyline in the Rat Brain

“…Nevertheless, as has already been stated, in the present study the reductions in in vivo tyrosine hydroxylase activity determined after acute treatment with clorgyline were still maintained after the 14-day treatment with this drug. This persistent reduction could be a consequence of the inhibition of the synthesis provoked by increased levels of the end product of the biosynthetic route [42] or due to a reduction in the expression of tyrosine hydroxylase in the rat brain, as has been found after chronic treatment with tricyclic antidepressants, MAO inhibitors, and selective inhibitors of the serotonin uptake [43][44][45]. Thus, it has been suggested that the change in the expression of tyrosine hydroxylase could be a common mechanism of adaptation after chronic treatment with drugs which increase neurotransmitter availability [43].…”

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

“…Cellular DA content is mainly within vesicles (Mosharov et al, 2006), and since norepinephrine (NE) is produced exclusively within vesicles by the action of DA-b-hydroxylase acting on DA taken up from the cytoplasm, enhanced vesicular uptake would be expected to increase cell contents of endogenous DA and NE. MAO inhibition may also act indirectly to decrease DA synthesis via enhanced feedback inhibition exerted by accumulation of DA in the cytoplasm (Ames et al, 1978;Laschinski et al, 1986;Gordon et al, 2008). Since DOPA is the immediate product of enzymatic hydroxylation of tyrosine, decreased tyrosine hydroxylase activity would be expected to attenuate DOPA production (Goldstein et al, 1987;Kvetnansky et al, 1992).…”

Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite

“…Studies have demonstrated the ability of DOPAL to covalently modify Lys residues via the aldehyde (Rees et al 2009), forming a Schiff-base structure predicted to interfere with normal protein function. Currently, specific protein targets of DOPAL are unknown, but previous studies have revealed that catechols and other DA-metabolism products interact with and inhibit tyrosine hydroxylase (TH), the rate-limiting step in DA synthesis (Laschinski et al 1986, Xu et al 1998). …”