I-dopa

A crucial achievement significantly stimulated the development of the investigation in the field of homogeneous enantioselective catalysis. The Knowles group established a method for the industrial synthesis of I-DOPA, a drug used for the treatment of Parkinson s disease. The key step of the process is the enantiomeric hydrogenation of a prochiral enamide, and this reaction is efficiently catalyzed by the air-stable rhodium complex [Rh(COD)((PP)-CAMP)2]BF4 (Scheme 1.12). 

This achievement was unique in two respects 1) it was the first example of industrial application of a homogeneous enantioselective catalysis methodology and 2) it represented a rare example of very quick convergence of basic knowledge into commercial application. The monophosphine ligand CAMP was shortly replaced by the related diphosphine ligand DIPAMP which improved the selectivity for the I-DOPA system up to 95% ee [45]. 

Percentage (%) relative to the rate of decarboxylation of i.-dopa into dopamine. 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

Semi-synthetic from testosterone yielding testosterone per esterases Metabolite of i-Dopa... 

Scheme 5-25 Decarboxylation of i-dopa in the CNS to yield the active drug dopamine.

Figure 2.56 Monsanto process for the synthesis of i-Dopa by asymmetric hydrogenation. Source adapted from Knowles [315].

High solubility - high permeability [e.g. Metoprolol, i-Dopa)... 

Table 4.3 i -DOPA/i.-tyrosine ratio in plasma/semm of melanoma patients... 

Dopamine agonists are i-dopa-sparing and decrease response fluctuations but are more likely to cause psychiatric symptoms such as hallucinations. 

The BS reaction is an excellent method for the introduction of radioactive fluorine-18 into molecules of biological interest. Examples include 18F-labeled haloperidol (IS),54 fluconazole (24),55 5-fluoro-I-dopa (25), amino acids,578 and 5-fluorouracil. 

Moclobemide has a negligible capacity to increase dopaminergic neurotransmission, but studies so far have revealed no significant interactions or major adverse side-effects when moclobemide is co-administered with i-dopa. 

FIGURE 27.5 Tyrosine is the biosynthetic precursor to a number of neurotransmitters. Each transformation is enzyme-catalyzed. Hydroxylation of the aromatic ring of tyrosine converts it to 3,4-dihydroxyphenylalanine (i-dopa), decarboxylation of which gives dopamine. Hydroxylation of the benzylic carbon of dopamine converts it to norepinephrine (noradrenaline), and methylation of the amino group of norepinephrine yields epinephrine (adrenaline). 

Administration of theophylline enhances the TSH response to TRH (FI). Administration of estrogen to men also enhances the TRH-induced TSH release (F2), and in the intact human, females exhibit a greater response than males (02) (Fig. 4). Supraphysiological doses of corticosteroids suppress the TSH response to TRH (W4), and this inhibitory effect is also seen in patients treated with i-dopa (SIO). The administration of growth hormone-release inhibiting hormone (GH-RIH, somato-... 

Prolactin secretion by pituitary cell cultures is inhibited by GH-RIH, but to a lesser extent than GH (VI). GH-RIH does not appear to affect basal PRL levels in normal subjects, but it has been reported to lower PRL release by otherwise normal pituitary cells when its secretion has been elevated by hypothyroidism or by chronic administration of estrogens. It does not affect the fall in PRL produced by i-dopa (S8) nor the rise in PRL resulting from insulin-induced hypoglycemia (H3) or thyrotropin-releasing hormone (Cl). Further critical studies of the effect of GH-RIH on basal circulating PRL levels are required. 

Catecholamines 104 Mixtures of epinephrine and i-dopa at the micromole per liter level are resolved by formation of the corresponding aminochromes. Stopped-flow mixing... 

---