Dopamine formation

COMT inhibitors rescue l-dopa and improve the brain entry of L-dopa by decreasing 3-OMD formation in peripheral tissues. The dose of L-dopa could be decreased, compared with the present combination therapy. Dose interval of L-dopa could also be prolonged. Further, COMT inhibitors should decrease fluctuations of dopamine formation in the brain. 

QUESTION How do you imagine that both a receptor antagonist and an uptake inhibitor would block the effects It would seem that if dopamine is involved, it would either be acting on a membrane receptor or inside, but not both. I would also like to ask a more specific question. You showed that the alpha MT protected effect could be reversed by dopa. And I think you imagined that that was because of dopamine formation. But have you tried dopamine agonists to see if they would antagonize either the protective effect of alpha methyltyrosine or, particularly, the protective effect of the dopamine antagonists to try to verily that those protective effects really have to do with blockade of a dopamine receptor as opposed to some other possibility ... 

Hiroi T, Imaoka S, Funae Y. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun 1998 249(3) 838—843. 

Figure 9.6 The rate of dopamine formation using the homogenate of rat cerebral cortex as enzyme at 37°C. The incubation system contained 0.5 mg of rat cerebral cortex. (From Nagatsu et al., 1979.)...

Schyman P, Lai W, Chen H, Wang Y, Shaik S (2011) The directive of the protein how does cytochrome P450 select the mechanism of dopamine formation J Am Chem Soc 133 7977-7984... 

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are as.sociated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of diis last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Dealkylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9NHC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21]. 

An additional benefit of COMT inhibitors can be found in positron emission tomography (PET) studies. In PET, using 6-[18F]-fluoro-L-dopa (6-FD) to visualize the brain dopamine metabolism, the peripheral formation of 3-0-methyl-6-[18F]-fluoro-L-dopa (3-OMFD) by COMT is harmful. 3-OMFD contaminates the brain radioactivity analysed since it is easily transported like 3-OMD to the... 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

Rocheville, M, Lange, DC, Kumar, U, Patel, SC, Patel, RC and Patel, YC (2000) Receptors for dopamine and somatostatin formation of hetero-oligomers with enhanced functional activity. Science 288(5463) 154-157. 

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H2O along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of its high levels of active iron and the low concentration of transferin to bind it. This potential toxic process could be enhanced by extra DA formed from levodopa in the therapy of PD (see Olanow 1993 and Olanow et al. 1998)...

Kobayashi, N. et al., Formation and occurrence of dopamine-derived betacyanins. Phytochemistry, 56, 429, 2001. 

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

The beneficial effect of deprenyl in Parkinson s disease was su ested to be in part due to its effect on increasing the levels of SOD activity in several brain regions (Carrillo et al., 1993). Deprenyl is known to inhibit monoamine oxidase type B, which results in a reduction in hydrogen peroxide formation by blockade of the oxidative deamination of dopamine. That is believed to be the major mechanism of action of this drug in inhibiting the progression of Parkinson s disease. 

COMMENT We feel that it is due to the formation of 5,6-DHT in the eortex. These cells are indeed innervated by serotonin cells and, as a matter of fact, we have an experiment that is being published in Brain Research where we show that if we injeet 5,6-DHT into the ventricles, we ean produce exactly the same type of degeneration in the pyramidal cells, due to the formation of the 5,6 from the 5-hydroxytryptamine. We are exploring the possibility of it being another catecholamine in addition to dopamine, so I think both of those may be helpful in answering your question. 

The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with PD lose dopamine neurons in the substantia nigra, which is located in the midbrain within the brain stem. The substantia... 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)] (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)[ (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert) and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott Hobson, 2002 Jones, 2003). The following neurotransmitters function to promote W (1) acetylcholine (ACh LDT/PPT, BFB) (2) noradrenaline (NA LC) (3) serotonin (5-HT DRN, MRN) (4) histamine (HA TMN) (5) glutamate (GLU mPRF, BFB, thalamus) (6) orexin (OX LH) and (7) dopamine (DA VTA, SNc) (Zoltoski et al, 1999 Monti, 2004). 

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