A-Methyl-m-tyrosine

Compound 10, representing a series of NRIs structurally similar to reboxetine, has been reported to be a potent and selective inhibitor of NET (K-, — 3.2 nM) [24], In an a-methyl-m-tyrosine (a-MMT)-induced cortical NE depletion model in rats, 10 showed dose-dependent activity after oral administration with a measured ED50 of 18mg/kg. WAY-256805 (11), an NRI, was recently reported to be efficacious in the mouse tail suspension model [25]. 

P.A. Shore, D. Busfield, H.S. Alpers, Binding and release of metaraminol Mechanism of norepinephrine depletion by a-methyl-m-tyrosine and related reagents, J. Pharmacol. Exp. Ther. 146 (1964) 194-199. 

Amino Acid Enzyme Inhibitors - A comparative clinical study of the antihypertensive effects elicited by intravenous injection of a-methyldopa and a-methyl-m-tyrosine has shown, contrary to previous reports, that the latter agent has a longer duration of action in essential hypertonia and also a more pronounced orthostatic effect.2S... 

The antihypertensive effects of a-methylated catecholamine analogs have been studied.In renal hypertensive rats, prolonged treatment with a-methyldopa, a-methyl- m-tyrosine, a-meth-yltyrosine or metaraminol produces dose-dependent decreases in blood pressure and dose-dependent depletion of myocardial catecholamines. The same order of relative activities was found in regard to noradrenaline depletion and antihypertensive effect, but there was no relationship between the degree of catecholamine depletion and the intensity of the hypotensive effect. 

Tyrosine is converted to dopa by the cytoplasmic enzyme tyrosine hydroxylase. This is the rate-limiting step 5 x 10 M) in DA synthesis, it requires molecular O2 and Fe + as well as tetrahydropterine (BH-4) cofactor and is substrate-specific. It can be inhibited by a-methyl-p-tyrosine, which depletes the brain of both DA and NA and it is particularly important for the maintenance of DA synthesis. Since the levels of tyrosine are above the for tyrosine hydroxylase the enzyme is normally saturated and so it is not possible to increase DA levels by giving tyrosine. 

Langen KJ, Muhlensiepen H, Holschbach M, Hautzel H, Jansen P, Coenen HH. Transport mechanism of 3-[ I]iodo-a-methyl-L-tyrosine in a human glioma cell line comparison with [ H-methyl]-L-methionine. J Nucl Med 2000 41 1250-1255. 

Many NRPs such as cyclosporin, complestatin, actinomycin, and chondramide contain N-methyl amides. M-Methyl transferase (N-MT) domains utilize S-adenosylmethionine (SAM) as a cofactor to catalyze the transfer of the methyl group from SAM to the a-amine of an aminoacyl-S-PCP substrate. The presence of M-methylamides in NRPs is believed to protect the peptide from proteolysis. Interestingly, N-MT domains are incorporated into the A domains of C-A-MT-PCP modules, between two of the core motifs (A8 and A9). MT domains contain three sequence motifs important for catalysis. ° 0-Methyl transferase domains are also found in NRPSs and likewise use the SAM cofactor. For instance, cryptophycin and anabaenopeptilide synthetases contain 0-MT domains for the methylation of tyrosine side chains. These 0-MT domains lack one of the three core motifs described for N-MT domains. ... 

K.J. Langen, H. Muhlensiepen, M. Holschbach, H. Hautzel, P. Jansen, H.H. Coenen, Transport mechanisms of 3-[123l]iodo-alpha-methyl-L-tyrosine in a human glioma cell line Comparison with [3H]methyl]-L-methionine, J. Nucl. Med. 41(7) (2000) 1250-1255. 

The following were administered separately to P. cyclopium [carboxyl- and [ N]-anthranilic acid, phenylalanine with labels at positions 1,2, and 3, and also N-labelled phenylalanine and [methyl- C]methiomne. The results show an intact incorporation of all the atoms of phenylalanine and anthranilic acid into both (49) and (50), with L-phenylalanine preferred over the D-isomer. The iV-methyl group originates from the S-methyl group of methionine. The cyclic dipeptide formed from these two amino-acids is presumably an intermediate on the pathway to the alkaloids. As phenylalanine serves as a precursor for cyclopenol, the origin of the hydroxy-group is by meta-hydroxylation of phenylalanine. Further, m-tyrosine and tyrosine are only unspecific precursors. 

Glover, R. T, Angiolieri, M., Kelly, S., Monaghan, D. T, Wang, J. Y, Smithgall, T. E., and Buller, A. L. (2000). Interaction of the A-methyl-D-aspartic acid receptor NR2D suhunit with the c-Abl tyrosine kinase./. Biol. Chem. 275, 12725-12729. 

A methanolic soln. of methyl L-tyrosinate hydrochloride and triethylamine added to a stirred soln. of methyl 2-0-acetyl-4,6-0-benzylidene-3-deoxy-3-nitro-/5-gluco-pyranoside, and allowed to stand 4 hrs. at room temp. methyl N-(methyl 4,6-0-benzylidene-2,3-dideoxy-3-nitro- -D-glucopyranosid-2-yl)-L-tyrosinate. Y 78%. F. e. s. F. J. M. Rajabalee, Synthesis 1972, 318 carbohydrate 1,2-nitramines, without triethylamine, s. Carbohyd. Res. 26, 219 (1973). 

Weber W, Wester H, Grosu A, Herz M, Dzewas B, Feldmann H, MoUs M, Stoecklin G, Schwaiger M. 0-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C] methionine uptake in brain tumors initial results of a comparative PET study. Eur J Nucl Med 2000 27 542-549. 

It is not known if m-tyrosine can be converted to l-DOPA by a cell-free extract of a species susceptible to m-tyrosine. If so, would the process be highly efficient in vivol Synthetic proherbicides, such as diclofop-methyl [11], that are inactive at the molecular target site are much more effective when applied to intact plants than the active molecule to which they are converted in vivo. This is due to superior cuticular and cellular uptake of the proherbicide. Some potent natural phytotoxins from microbial origin, such as hydantocidin and 2,5-anhydro-D-glucitol, are protoxins [170-171]. 

Considerable effort has gone into the synthesis of aminoacid glycosides mainly because of their significance in glycopeptide chemistry. Reaction of the dimer of tri-Q-acetyl-2-deoxy-2-nitroso-a-D-glucopyranosyl chloride with methyl M substituted-L-serinate (and L-threoninate and L-tyrosinate) gave mixed anomers of the oximes (9), and their deacylated products on deoximation, reduction and reacetylation afforded the corresponding q-d-... 

Moon, I. S., Apperson, M. L. and Kennedy, M. B. The major tyrosine-phosphorylated protein in the postsynaptic density fraction is N-methyl-D-aspartate receptor subunit 2B. Proc. Natl Acad. Sci. U.S.A. 91 3954-3958,1994. 

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