Phenylethylamine, hydroxylation

Fig. 18. Hypothetical scheme for phenylethylamine hydroxylation involving simultaneous attack of oxygen by substrate and reducing agent.

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

Tyramine is produced by decarboxylation of tyrosine and is present in the CNS in higher (threefold) concentrations than m-tyramine, the hydroxylated derivative of phenylethylamine. In the periphery / -tyramine is easily hydroxylated to octopamine, which has some direct effects on ai adrenoceptors, unlike tyramine which functions by releasing NA. When tested on central neurons tyramine always produces the same effects as NA but they are slower and less marked, implying an indirect action. By contrast octopamine often produces the opposite effect to NA and it is probable that octopamine may have a functional role in the invertebrate CNS where it is found in higher concentrations (5pg/g) than in the mammalian brain (0.5ng/g). Neither tyramine nor octopamine have distinct behavioural effects, unlike phenylethylamine,... 

On comparing the activities of the five compounds for which numerical estimates are available in all three assays (synephrine, octopamine, phenylethanolamine, norepinephrine and tyramine) the rank orders of potency in the three systems are Crayfish, 1,2,3t4,5 Cockroach, 2,1,3,4,5 Locust 1,2,3t5,4. This indicates a basic similarity in the responses of these preparations. In each case it was found that ring hydroxylation of the phenylethylamine nucleus was not essential for activity, although p-hydroxylation does yield the best activity. This is particularly evident in the crayfish study where a-MAMBA (a-methylaminomethyl benzyl alcohol), the analog of synephrine which lacks ring substitution, was one of the most active compounds tested, and 3-phenylethanolamine, the corresponding analog of OA, is almost as active as OA. The base compound for this series, phenylethylamine, also shows appreciable activity, but only in the crayfish assay. 

Dobutamine Dobutamine, ( ) 4-[2(4 -hydroxyphenyl)-l-methylpropyl]-3,4-dihydrox-yphenylethylamine (11.1.31), differs significantly from all of the presented drugs in terms of structure, the main difference being the absence of a hydroxyl group at the )3-carbon atom of the phenylethylamine moiety of classic sympathomimetics. The second considerable difference from the examined drugs is the presence of p-hydroxyphenyl-iso-buty-lamine group as a terminal amine substituent. 

This is a tetrameric copper-containing glycoprotein, which catalyzes the conversion of dopamine into norepinephrine, a hormone/neurotransmitter, and also the hydroxylation of a number of substituted phenylethylamines.1401 1403 Consideration of this enzyme has been hindered by uncertainty over the stoichiometry of binding of copper, and, until recently, there seemed to be good evidence for four copper ions per molecule.1 4 However, there is now convincing support for a stoichiometry of eight copper ions per molecule, with two per subunit.1405,1406 This conclusion is based upon analysis and titration methods. 

Several alkaloids of the phenylethylamine, morphine and Ipecacuanha classes can be detected directly with DNS-C1 [121-124]. This reagent reacts with the primary and secondary amino groups or phenolic hydroxyl groups of the alkaloids to form highly fluorescent derivatives, nanogram amounts of which may be detected after chromatographic separation. 

Chemical structures of catecholamines produced naturally in humans are shown in Figure 29-1. Epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine are phenylethylamines with hydroxylation on positions three and four of the benzene ring and with an ethylamine moiety on position one. Hydroxyl and methyl substitution on the... 

Introduction of hydroxyl or methoxyl group, or an unsaturation in isoquinoline and methox-yl group in B-phenylethylamines, resulted in an increase in the retention time. It could again be conjectured that the increase in polarity of the derivatives caused the increase in adsorption on the liquid phase. 

Resolution of the enantiomeric mixture can be performed at this step, after acetylation of the secondary hydroxyl, by separation of diastereoisomeric salts 62 and 62a with 1-phenylethylamine. 

Since the phenylethylamines 312 produced by these decarboxylases are substrates for systems containing dopamine jS-hydroxylase (EC 1.14.17.1), the availability of 7>R and 3S isotopically labeled samples of the aromatic amino acids has allowed the stereochemistry of the hydroxylation of dopamine 313 to yield norepinephrine 314 to be studied (Scheme 83). It was shown that the 3-pro-S hydrogen, Hg, was lost from phenylalanine 297a in the process and that the hydroxylation yielding 314 therefore occurred with retention of configuration (319). 

Dopamine -hydroxylase catalyzes the side-chain hydrox-ylation of dopamine and other phenylethylamine derivatives. Ascorbic acid serves as a specific electron-donating cofactor. The enzyme from bovine adrenal glands contains and a smaller amount of Cu. When the enzyme oxidizes ascorbate to dehydroascorbate, most of the is reduced to Cu Added substrate is hydroxylated, and Cu is reoxidized to Cu This indicates that most of the protein-bound Cu undergoes cyclic reduction and oxidation during hydroxyhtion. The results also rule out an oxygen-carrier function for ascorbate. The possibility that a p-substituted hydroperoxide of the substrate is formed as an intermediate in the reaction has been examined with the use of 13,13 -tritium-labelled substrate. The results indicate that such an intermediate is unlikely. 

Other methyl-substituted phenylethylamines (phenylisopropylamines). such as (S)-(+)-amphetamine and (S)-(+)-methamphetamine, which lack both ring substituents I side-chain hydroxyl, are sufficiently lipophilic to cross the blood-brain barrier readily and cause dramatic CNS stimulation, which gives them serious abuse... 

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