N -carbamoyl-2-O-methyltyrosine-oxytocin and 1-6 deamino cystathionine-2-O-methyltyrosine oxytocin: two antagonists of oxytocin on amphibian epithelial cell receptors.
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Animals↗
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Renal lesions induced by alpha-methyltyrosine methylester and alpha-methyltyrosine.
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Animals↗
Prolactin and growth hormone synthesis: effects of perphenazine, alpha-methyltyrosine and estrogen in different thyroid states.
The effects of thyroid hormones on prolactin (PRL) and growth hormone (GH) synthesis by the rat anterior pituitary gland were assessed in vitro. A marked reduction (84-87%) in the rate of H3-leucine incorporation into GH was evident 2-4 weeks after thyroidectomy, while incorporation into PRL was 52-71% less than that measured in glands from intact rats. A single injection of T4 (200 mug/kg) administered to thyroidectomized (THX) rats 48 hr before sacrifice significantly increased incorporation into both pituitary hormones, although the stimulation of GH synthesis was much more dramatic. Perphenazine, alpha-methyltyrosine and estrogen enhanced the rate of PRL synthesis in intact rats. Thyroid ablation did not affect the response to perphenazine, but significantly increased the response to alpha-methyltyrosine and estrogen. On the other hand, administration of T4 to THX rats receiving perphenazine, alpha-methyltyrosine or estrogen diminished the stimulatory influence of these treatments on PRL synthesis. Perphenazine, alpha-methyltyrosine and estrogen had no effect on the rate of GH synthesis in THX rats, nor did they alter the ability of T4 to restore GH synthesis in these animals. These results indicate that GH synthesis in the rat is dependent upon thyroid hormones and support the concept that these hormones exert their stimulatory effect directly on pituitary somatotrophs. Pituitary lactotrophs, however, appear to retain much of their capacity to synthesize PRL under conditions of thyroid deficiency. The changes in pituitary PRL levels and synthesis rate induced by thyroid ablation might reflect differences in the number rather than the activity of these cells.
Animals↗
Alpha-methyltyrosine blocks the expression of rotation classically conditioned with apomorphine.
Rats with unilateral 6-hydroxydopamine lesions of substantia nigra rotate (circle) when placed, undrugged, in the environment in which they have previously been treated with apomorphine. This conditioned rotation, like the unconditioned rotation which acutely follows the administration of apomorphine, is directed away from the side with the lesion, i.e., the rotation is contralateral. Here, rats that had been administered apomorphine weeks earlier were tested, in a crossover design, for the expression of conditioned rotation following treatment with saline and with alpha-methyltyrosine. When administered four hours prior to testing, 100 mg/kg alpha-methyltyrosine significantly antagonized the expression of classically conditioned rotation. In a second group of animals, alpha-methyltyrosine had no effect on the unconditioned rotation induced by 0.05 mg/kg apomorphine.
Animals↗
Failure of alpha-methyltyrosine to prevent hypertensive crisis in pheochromocytoma.
Sudden onset of a hypertensive crisis occurred shortly after induction of anesthesia in a patient with malignant pheochromocytoma, despite preoperative medical preparation with alpha-methyltyrosine (alpha-methyl-p-tyrosine) and propranolol hydrochloride. Other investigators have advocated alpha-methyltyrosine as the medical therapy of choice in the preoperative preparation of patients with pheochromocytoma. This case emphasizes the caution that should be exercised when using alpha-methyltyrosine preoperatively, without concurrent alpha-adrenergic blocking agents, to prevent intraoperative hypertensive crisis.
Adrenal Gland Neoplasms↗
Effects of locally applied dopamine to the nucleus accumbens on the motor activity of normal rats and following alpha-methyltyrosine or reserpine.
The motor activity of rats was investigated following bilateral application of various doses (0--80 micrograms) of dopamine to the nucleus accumbens. A high dose (80 micrograms) of dopamine increased the motor activity of normal as well as alpha-methyltyrosine- and reserpine-treated rats. It also increased the late motor activity (6--9 min) of normal rats, probably due to stimulation of postsynaptic dopamine receptors. Lower doses (10--40 micrograms) of dopamine suppressed initial (0--3 min) motor activity of normal rats, perhaps due to stimulation of dopamine autoreceptors on the dopamine nerve terminals in the nucleus accumbens with a subsequent inhibition of dopamine neurotransmission. An intermediate dose (40 micrograms) of dopamine was able to restore the motor activity of alpha-methyltyrosine-treated but not of reserpine-treated rats at all time intervals. This difference, indicating a restoration of the normal pattern of habituation by dopamine only in animals pretreated with alpha-methyltyrosine, suggests that normal behaviour is dependent on release of dopamine by nerve impulses.
Animals↗
Effect of p-chlorophenylalanine and alpha-methyltyrosine on the antinociceptive effect of antidepressant drugs.
The role of para-chlorophenylalanine and alpha-methyl-DL-p-tyrosine in the antinociceptive effects of the intracerebroventricular administration of the antidepressant drugs clomipramine, zimelidine, imipramine and maprotiline was studied using the acetic acid writhing test in mice. The results demonstrated an antinociceptive effect for all these antidepressants. Pretreatment with para-chlorophenylalanine significantly reduced the antinociception induced by the ED50's of imipramine and maprotiline, and did not modify the effects of zimelidine and clomipramine, pretreatment with alpha-methyl-tyrosine did not modify the antinociception induced by these drugs except maprotiline. Pretreatment with para-chlorophenylalanine plus alpha-methyltyrosine significantly reduced the antinociceptive effect of all the antidepressants tested. The main finding of the present study is that the association of para-chlorophenylalanine plus alpha-methyltyrosine reduced the antinociceptive action of all the antidepressants. This means that critical levels of both 5-HT and NA are responsible for mediating the antinociceptive effects of antidepressants on the writhing test in mice.
Acetates↗
Effects of amfonelic acid, alpha-methyltyrosine, Ro 4-1284 and haloperidol pretreatment on the depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in 4 daily s.c. injections to mice resulted in marked depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) 1 week after the last dose. Pretreatment of mice with alpha-methyltyrosine or Ro 4-1284 to deplete dopamine prior to MPTP injection did not prevent these effects of MPTP, nor did pretreatment with haloperidol, a dopamine receptor antagonist. The depletion of striatal dopamine by MPTP in mice therefore differs from the persistent depletion of striatal dopamine by amphetamine in iprindole-treated rats, which is prevented by pretreatment with either alpha-methyltyrosine or haloperidol. The depletion of dopamine, DOPAC and HVA in mouse striatum by MPTP was totally prevented by pretreatment with amfonelic acid, an inhibitor of dopamine uptake. This finding suggests that these effects of MPTP, like those of amphetamine in iprindole-treated rats, are dependent upon a functional transport system into the dopamine neuron.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Morphine enhancement of shuttle avoidance prevented by alpha-methyltyrosine.
Rats were given 6 days of training (180 trials) to make a two-way (shuttle) avoidance response. "Poor performers" making less than 50% avoidances in the 6th block of 30 tials were given drug treatments on the next 2 days. Both morphine sulfate (15 mg/kg) and d-amphetamine sulfate (1 mg/kg) increased the avoidance level by 70-100%. Prior treatment with alpha-methyltyrosine (50 mg/kg) prevented the effects of both drugs. Nalorphine hydrochloride (5 mg/kg) also blocked the effect of morphine. The action of alpha-methyltyrosine to block enhancement of avoidance is taken to indicate that this effect of morphine is attributable to a catecholamine-dependent excitatory component of its activity profile.
Animals↗
Synthesis of (2S,3R)-beta-methyltyrosine catalyzed by tyrosine phenol-lyase.
A one-step enzymatic synthesis of the conformationally restrained tyrosine analog (2S,3R)-beta-methyltyrosine is reported. This synthesis extends the preparative chemistry associated with tyrosine phenol-lyase. This beta-methyltyrosine derivative was shown to be an efficient protein tyrosine kinase substrate, suggesting that conformational restraint may ultimately be used to enhance tyrosine kinase recognition of substrates.
Catalysis↗
The effects of reserpine, alpha-methyltyrosine, and L-3,4-dihydroxyphenylalanine on brain tyrosine transaminase.
The effects of a variety of pharmacological and physiological manipulations on the activity of hepatic tyrosine transminase have been extensively investigated. Brain tyrosine transaminase, however, has received only limited attention. Since tyrosine transaminase may be important in the regulation of catecholamine biosynthesis in the brain, the effects of agents affecting catecholamine storage and synthesis on brain tyrosine transamination were investigated. Transamination in the 12,000 x g fraction was measured by a radioactive procedure. alpha-Methyltyrosine and reserpine, agents which deplete brain catecholamines, decreased tyrosine transaminase activity. Administration of the catecholamine precursor, L-3,4-dihydroxyphenylalanine to the reserpine-and alpha-methyltyrosine-treated rats elevated the tyrosine transaminase activity to normal. The possible implications of these findings in the regulation of the biosynthesis of the catecholamines are discussed.
Animals↗
Accumulation of radioiodinated L-alpha-methyltyrosine in pancreas of mice: concise communication.
L-3-iodo-alpha-methyltyrosine, labeled with either I-131 or I-123, has a high pancreatic specificity in mice. A pancreas-to-liver ratio of 8.6 +/- 2.7 is observed during the first hour after i.v. injection. Accumulation is also prominent in the kidneys, but excretion of the radioagent is rapid, 50% of the activity being eliminated during 90 min. Compared with L-[75Se]selenomethionine, the compound currently used for pancreatic imaging, L-3-[123I]or[131I]iodo-alpha-methyltyrosine has a higher pancreas-to-liver ratio, a shorter physical half-life and biological half-time, and better decay characteristics.
Animals↗
Synthesis of [alpha-methyltyrosine-4]angiotensin II: studies of its conformation, pressor activity, and mode of enzymatic degradation.
Modifications in angiotensin II and its antagonistic peptides that should have increased in vivo half-lives but not reduced biological activity were studied by determining the effect of alpha-methylation of the tyrosine in position 4. [alpha-Methyltyrosine-4]angiotensin II, synthesized by the solid-phase procedure, showed 92.6 +/- 5.3% pressor activity of angiotensin II. Incubation with alpha-chymotrypsin for 1 hr indicated absence of degradation although, under the same conditions, angiotensin II was completely degraded to two components. Comparison of the 1H NMR spectra in aqueous solution and the circular dichroism spectra in trifluoroethanol of angiotensin II and [alpha-methyltyrosine-4]angiotensin II suggested that alpha methylation of the tyrosine residue in angiotensin II does not lead to major changes in the overall solution conformation. These results are in contrast to those obtained with N-methylation in position 4, which drastically reduced the biological activity and produced remarkable changes in the peptide backbone and a severe limitation in rotational freedom of the side chains in tyrosine. Thus, it may be possible to synthesize potent angiotensin II analogs that have greater resistance to enzymatic degradation by alpha-methylation in position 4 (or 5) and simultaneous suitable modification at the NH2 and COOH termini.
Angiotensin II↗
Preliminary observations of malignant melanoma therapy using radiolabeled alpha-methyltyrosine.
A strategy for cancer therapy using astatine-211-labeled alpha-methyltyrosine (211At-AMT) was studied in cultured B16 melanoma cells and compared to the radiotoxicity of iodine-125-labeled iododeoxyuridine (125IUdR), a thymidine analogue. Both 125I and 211At deliver lethal doses of irradiation to melanoma cells when administered as 125IUdR and 211At-AMT. The alpha decay of astatine-211 is more effective however, needing only a fraction of the cellular radioactivity of 125IUdR to effect comparable clonogenic survival. Compared with 125IUdR, 125I-AMT is not cytotoxic because the range of the low energy electrons released does not interact with DNA. Uptake of radiolabeled AMT by melanotic cells is enhanced by theophylline. This preliminary evidence suggests that 211At-labeled melanin precursors may be exquisitely cytotoxic to B16 melanoma cells.
Astatine↗
Antipsychotic treatment with alpha-methyltyrosine in combination with thioridazine: prolactin response and interaction with dopaminergic precursor pools.
The antipsychotic effect of alpha-methyltyrosine (alpha-MT) in combination with thioridazine was investigated by means of rating scales for "social behaviour" and "mental symptoms". The clinical effect was also evaluated in relation to the serum concentrations of alpha-MT and thioridazine and to the increase in prolactin secretion in response to the interaction with hypothalamic dopaminergic mechanisms. The interactions between the serum levels of alpha-MT and those of the transmitter precursors phenylalanine and tyrosine were analysed. The results confirmed the ability of alpha-MT (2 g/day) to potentiate the antipsychotic effect of thioridazine, whereby the dose of neuroleptic drug required to control psychotic symptoms may be markedly reduced. None of the four patients who completed the trial showed side effects that could be ascribed to alpha-MT. The antipsychotic effect of thioridazine, alone or in combination with alpha-MT, correlated well with the prolactin response in the individual patient. No important interference with serum phenylalanine or tyrosine levels was noted during treatment with alpha-MT.
Aged↗
alpha-Methyltyrosine blocks methylamphetamine-induced degeneration in the rat somatosensory cortex.
Neurochemical and histological studies suggest that methylamphetamine (MA) administered continuously or in high doses is toxic to dopaminergic and serotonergic nerve terminals. Degeneration of the dopaminergic or serotonergic cell bodies themselves has not been reported, however. In the present study, administration of a single 100 mg/kg dose of MA was toxic to a subpopulation of neurons in the somatosensory cortex, an area of the brain which does not contain catecholaminergic or serotonergic cell bodies. This dose of MA also produced a long-lasting depletion of serotonin (5-HT) but not norepinephrine in the somatosensory cortex. Dopamine levels in the somatosensory cortices of control animals were virtually undetectable and therefore were not studied further. Administration of alpha-methyltyrosine (alpha-MT), a catecholamine synthesis inhibitor, prior to the injection of MA blocked both the depletion of 5-HT and the degeneration of cortical perikarya produced by MA alone. Since the MA-induced depletion of 5-HT and the MA-induced degeneration of cortical perikarya are correlated, we suggest that the serotonergic system may be involved in the toxic effects of MA on the cortical neurons.
Animals↗
Synthesis of isomers of 18F-labelled amino acid radiopharmaceutical: position 2- and 3-L-18F-alpha-methyltyrosine using a separation and purification system.
To diagnose cancers with radiolabelled amino acid using positron emission tomography, we have constructed a separation and purification system for the production of L-18F-alpha-methyltyrosine (L-18FAmT). This system could provide radioprotection and consistent production of L-18FAmT. L-18FAmT was synthesized and purified and the efficiency of the system was examined. The radiochemical yield of L-18FAmT was 20.3 +/- 5.1% (n = 5) based on the radioactivity trapped in the reaction vessel. The radiochemical purity was greater than 99.4 +/- 0.3% (n = 5). The radiochemical stability in phosphate-buffered saline and human plasma was examined and little decomposition was observed by HPLC analysis. Our results indicate that the separation and purification system gave simple and quick synthesis of L-18FAmT with a large reduction in radiation exposure and consistent production of L-18FAmT.
Amino Acids↗
Reversal of alpha-methyltyrosine-induced hypoactivity by 6-(R)-5,6,7,8-tetrahydro-L-erythrobiopterin (R-THBP) in mice.
The effects of peripheral administration of 6-(R)-5,6,7,8-tetrahydro-L-erythrobiopterin dihydrochloride (R-THBP), a natural cofactor for tyrosine and tryptophan hydroxylases, were investigated in mice treated with a competitive inhibitor of tyrosine hydroxylase, alpha-methyltyrosine (alpha-MT). A subcutaneous dose of 250 mg/kg of alpha-MT decreased markedly both ambulatory activity and cerebral contents of norepinephrine, dopamine and their metabolites in mice. An intraperitoneal dose of 100 mg/kg of R-THBP, which did not alter ambulatory activities in normal mice, improved the hypoactivity in alpha-MT-treated mice. Moreover, R-THBP at intraperitoneal doses of 60 and 100 mg/kg inhibited the impairment of cerebral catecholamine metabolism induced by alpha-MT in mice. We suggest that the reversal of the alpha-MT effects by R-THBP might be due to reactivation of tyrosine hydroxylase in the central nervous system.
Animals↗