Tyrosine hydroxylase inhibitors

Therapeutic Function Tyrosine hydroxylase Inhibitor Chetnicel Name tt-Methyl-L-tyrosine Common Name Metirosine Structural Formula ... 

A second, more extensive experiment involved oral administration of three daily doses (100 mg/kg) of parachlorophenylalanine (PCPA). This tryptophan hydroxylase inhibitor (47), like reserpine, enhanced the behavioral effects of LSD (13) moreover, hypersensitivity occurred when 5-HT, but not other monoamine, concentrations were below normal in both forebrain and hindbrain (13). That is, effects were observed at 5 and 12 days (when 5-HT was depleted to 10-20% and 60-70% of normal) but not at 21 days (when 5-HT had returned to normal). Control experiments (13) indicated that (a) the interaction of PCPA, 5-HT, and LSD was probably not caused by generalized hyperactivity or hyperirritability sometimes seen after PCPA (73) (b) PCPA does not affect threshold doses of other psychoactive but nonserotonergic compounds, such as d-amphetamine (0.3 mg/kg) and (c) pretreatment with a-methylparatyrosine, a tyrosine hydroxylase inhibitor which depletes catecholamines rather than indoleamines, does not alter sensitivity to LSD. 

Inhibition of norepinephrine biosynthesis can be achieved quite well by chronic oral administration of the tyrosine hydroxylase inhibitor CH-methyl-p-tyrosine (LXII) but reduction in blood pressure was not achieved in patients with essential hypertension (77). Another potent inhibitor, 3-iodotyrosine (LXIII) was also inactive in man (78). Apparently, substantial reduction of norepinephrine (50-70%) is not enough to achieve the desired effect. 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine... 

Mechanism of Action A tyrosine hydroxylase inhibitor that blocks conversion of tyrosine to dihydroxyphenylalanine, the rate limiting step in the biosynthetic pathway of catecholamines. Therapeutic Effect Reduces levels of endogenous catecholamines. 

Dopamine synthesis inhibitors interfere with the enzymes involved, and are identical to those discussed in section 4.3.5 (e.g., a-methyltyrosine (4.74), a tyrosine hydroxylase inhibitor). In this case, aj-adrenergic receptor effects are irrelevant, and only the classical competitive inhibitory effect is of any consequence. 

Therapeutic Function Tyrosine hydroxylase inhibitor Chemical Name a-Methyl-L-tyrosine... 

Anden, N.-E. (1967) Effects of reserpine and a tyrosine hydroxylase inhibitor on the monoamine levels in different regions of the rat central nervous system. Eur. J. Pharmacol. 1, 1-5. 

During the past year several studies have appeared in the literature bearing on the relationship of 5-HT and/or its precursor to depression. Shopsin et al., in two studies, were able to show that the positive therapeutic response of depressed patients to imipramine 25 or tranylcyromine 28 could be reversed by co-administration of the tryptophan hydroxylase inhibitor PCPA (p-chlorophenylalanine). These same investigators could not show any effect of alpha-methyltyrosine, a tyrosine hydroxylase inhibitor, on the positive clinical response to imipramine. 25 These data seem to indicate that serotonin, rather than catecholamines, is involved in depression. 

Inhibition of DA synthesis by the tyrosine hydroxylase inhibitor MpT attenuates not only 6-OHDA formation and degeneration of striatal dopaminergic terminals, but also 5,6-DHT formation and the degeneration of serotonergic terminals and cell bodies of unknown neurotransmitter content in the somatosensory cortex (Commins and... 

Interesting central anti-amphetamine effects are described for tyros ie hydroxylase inhibitors such as a-methyl-tyrosine. Since norepinephrine depletors do not antagonize amphetamine and tyrosine hydroxylase inhibitors have little direct sedative effect, it is suggested that small but critical levels of norepinephrine at receptors are necessary for amphetamine to exert both its stimulant and anorexigenic effects. Whether this applies to other anorectic drugs remains to be determined. 

Excess NE normally subjects tyrosine uptake to feedback inhibition. Tyrosine conversion to dopamine can be inhibited by methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. 

Metyrosine is oc-methyl tyrosine, which competes with tyrosine for sites on tyrosine hydroxylase—the enzyme responsible for the rate-limiting step in catecholamine biosynthesis. Thus, it decreases catecholamine biosynthesis, resulting in a decrease in circulating levels of catecholamines. Metyrosine is a tyrosine hydroxylase inhibitor. 

PHE004 benzimidazole tyrosine hydroxylase inhibitor 1970JMC13 741... 

Numerous tyrosine hydroxylase inhibitors, chiefly of the phenylalkyl carboxylic acid type, have been described [101,128, 138, 139, 200, 257]. One of the most potent inhibitors in vitro, 3-iodotyrosine, proved inactive in man, probably because it is rapidly dehalogenated in vivo [72]. H22/54 has been found to be one of the most effective tyrosine hydroxylase inhibitors with catechol structure [44, 257]. The pyrroloisoxazole CL-65,263 and its derivatives represent a new type of tyrosine hydroxylase inhibitor [89, 243]. They lower blood pressure and cause... 

For example, chlorpromazine enhanced central catecholamine biosynthesis vivo by Increasing the hydroxylation of tyro-sinei07 10 Chlorpromazine also accelerated cerebral catecholamine depletion in rats pretreated with a tyrosine hydroxylase inhibitor. The latter experiments using hlstochemical... 

Tyrosine hydroxylase Inhibitors - Perhaps the greatest effort is being directed toward studies of the enzyme tyrosine hydroxylase which represents the rate limiting step in catecholamine synthesis. This enzyme catalyzes the conversion of tyrosine to DOPA and Is localized In the particulate fraction of the cell sedimenting at 16,000 x g. Inhibition of this enzyme has been found to be the most effective means of blocking the formation of norepinephrine. Much of the biochemistry of this and other enzymes associated with catecholamines was discussed at the Second Symposium on Catecholamines and published in 1966. Hundreds of compoumds have been examined for anti-tyrosine hydroxylase activity, but only a few exhibited Inhibitor activity vitro, and these were mainly analogues of tyrosine or its catechol metabolites. It has become apparent, however, that there is not always a relationship between vitro and to vivo activity. Of the many compounds thus far tested, two which have shown In vivo activity are a-methyl-1-tyroslne (a-MT) and H44/68 (the methyl ester-HCl of c MT), both acting as competitive antimetabolites of tyrosine. 

Their mechanism of lowering tissue levels of norepinephrine is not related to an interference of the uptake, storage or release of catecholamines. The administration of 05-MI results in a depletion of norepinephrine in various tissues of animals and a reduction in the synthesis of catecholamines by 70 percent in man. Although only the 1-isomer of OS-MI is active as a tyrosine hydroxylase inhibitor, the d-form potentiates the action of OS-MT, a phenomenon which has been postulated to occur as a result of an effect on membrane permeability. a-MI has served as a valuable experimental tool wherever the involvement of catecholamines has... 

McGeer al 3 found a group of 5-halogenated tryptophans to be highly effective as tyrosine hydroxylase inhibitors, dl-5-lodotryptophan produced a 50 percent inhibition at 12.5 x 10" M of rat brain homogenate activity. Burkard et al reported on the unexpected finding of a considerable activation of tyrosine hydroxylase by the tranquilizer chlor-promazine. Nyback al J also observed an increase in the accumulation of C -dopamine after administration of C -tyrosine in chlorpromazlne-pretreated rats. 

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