Fluorinated dihydroxyphenylserines as potential biological precursors of fluorinated norepinephrines.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Droxidopa”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Synthesis of 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine as potential in vivo precursors of fluorinated norepinephrines.
The title compounds were prepared by the aldol condensation of 3,4-dibenzyloxy-2-fluorobenzaldehyde and 4,5-dibenzyloxy-2-fluorobenzaldehyde with the oxazolidinone 2, a chiral glycine equivalent. Removal of the chiral auxiliary and blocking groups produced the target amino acids 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine (1b and 1c) in >98% ee.
Adrenergic Agonists↗
Effect of minor tranquillisers on hippocampal theta rhythm mimicked by depletion of forebrain noradrenaline.
Explore the source record for details and available documents.
Action Potentials↗
Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.
Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose tissue occurs in response to cold and overeating (diet induced), and there is an inverse relationship between diet-induced thermogenesis and obesity both in humans and in animal models. As a potential model for obesity, we generated mice that cannot synthesize noradrenaline or adrenaline by inactivating the gene that encodes dopamine beta-hydroxylase. These mice are cold intolerant because they have impaired peripheral vasoconstriction and are unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP1). The mutants have increased food intake but do not become obese because their basal metabolic rate is also elevated. The unexpected increase in basal metabolic rate is not due to hyperthyroidism, compensation by the widely expressed uncoupling protein UCP2, or shivering.
Adipose Tissue↗
Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system.
Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin. We recently showed that Gata3-directed lacZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Gata3 expression, except in thymus and the sympathoadrenal system. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants. We find here that null mutation of Gata3 leads to reduced accumulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine beta-hydroxylase, Dbh) mRNA, whereas several other SNS genes are unaffected. We show that Th and Dbh deficiencies lead to reduced noradrenaline in the SNS, and that noradrenaline deficiency is a proximal cause of death in mutants by feeding catechol intermediates to pregnant dams, thereby partially averting Gata3 mutation-induced lethality. These older, pharmacologically rescued mutants revealed abnormalities that previously could not be detected in untreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cells. Thus we have shown that Gata3 has a role in the differentiation of multiple cell lineages during embryogenesis.
Animals↗
DL-Threo-3,4-dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension.
DL-Threo-3,4-dihydroxyphenylserine (DL-DOPS) was given to six subjects with severe orthostatic hypotension (OH). On separate days each subject took either 600 or 800 mg DL-DOPS or placebo. DL-DOPS increased norepinephrine (NE) excretion 10,000% and urinary normetanephrine and dihydroxyphenylglycol excretion 400%. DL-DOPS, however, led to only slight increases in excretion of the major NE metabolites 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid. Only approximately 2.2% +/- 0.5% (range 0.65% to 3.8%) of the L-stereoisomer (L-DOPS), when given as DL-DOPS, is converted to NE in vivo over 24 hr. DL-DOPS did not affect either supine or upright blood pressure in our subjects. Our findings do not support reports that DL-DOPS may be therapeutically useful in OH.
Adult↗
Nature of the stimulation of biogenesis of cholesterol in the liver by noradrenaline.
1. Administration of noradrenaline increased the incorporation of [1-14C]acetate into hepatic sterols and the activity of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase. 2. The stimulation was observed at short time-intervals with a maximum at 4h and was progressive with increasing concentrations of noradrenaline. 3. Protein synthesis de novo was a necessary factor for the effect. 4. The stimulatory effect was not mediated through the adrenergic receptors, but appears to involve a direct action of the hormone within the hepatocyte.
Animals↗
Noradrenaline treatment of rats stimulates H2O2 generation in liver mitochondria.
Treatment of rats with noradrenaline stimulated H2O2 generation in liver mitochondria using succinate, choline or glycerol 1-phosphate as substrate. The dehydrogenase activity with either succinate or choline as substrate showed no change, whereas that with glycerol 1-phosphate increased. The effect was obtained with noradrenaline, but not with dihydroxyphenylserine. Phenoxybenzamine and yohimbine, but not propranolol, prevented the response to noradrenaline treatment. Phenylephrine could stimulate H2O2 generation, whereas isoprenaline had only a marginal effect. Theophylline treatment slightly decreased the generation of H2O2 in liver mitochondria, but treatment with pargyline, Ro4-1284 and dibutyryl cyclic AMP had little effect. These studies showed that noradrenaline might possibly be acting through the alpha 2-adrenergic system.
Animals↗
Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase.
Mice with a targeted disruption of the dopamine beta-hydroxylase (DBH) gene are unable to synthesize norepinephrine (NE) and epinephrine. These mice have elevated levels of dopamine in most tissues, although the levels are only a fraction of those normally found for NE. It is noteworthy that NE can be restored to normal levels in many tissues after a single injection of the synthetic amino acid precursor of NE, L-threo-3,4-dihydroxyphenylserine (DOPS). In other tissues, NE can be restored to normal levels after multiple injections of DOPS, whereas in the midbrain and cerebellum, restoration of NE is limited to 25-30% of normal. NE levels typically peak approximately 5 h after DOPS administration and are undetectable by 48 h. Epinephrine levels are more difficult to restore. The elevated levels of dopamine fall modestly after injection of DOPS. S(-)-Carbidopa, which does not cross the blood-brain barrier, inhibits aromatic L-amino acid decarboxylase and effectively prevents restoration of NE by DOPS in the periphery, while allowing restoration in the CNS. Ptosis and reductions in male fertility, hind-limb extension, postdecapitation convulsions, and uncoupling protein expression in dopamine beta-hydroxylase-deficient mice are all reversed by DOPS injection.
Animals↗
The norepinephrine precursor L-threo-3,4-dihydroxyphenylserine facilitates motor recovery in chronic stroke patients.
L-threo-3, 4-dihydroxyphenylserine (L-DOPS) is a precursor of norepinephrine. We reported that administration of L-DOPS to rats with ablation of the right sensorimotor cortex results in functional recovery from deficits in beam-walking performance. We al so reported that improvement in Fugl-Meyer Score (FMS) was significantly higher in an L-DOPS-treated group of chronic neurologically stable stroke patients than in a control group for 2 days. In the present study, 27 patients who had suffered from stroke more than one month previously and had exhibited no improvement in neurological deficits for at least one week were administered 300mg/day L-DOPS for 28 days with rehabilitation. FMS improved by 4.4 points (P< 0.001), 10m gait time was shortened by 16% (P< 0.001) and the cerebral blood flow of the lesion was increased (P< 0.03), after 28 days of drug administration. These findings suggest that L-DOPS is effective in restoring neurological deficit, which does not usually recover when only treated with rehabilitation therapy.
Adult↗
Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors.
Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine beta-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh(-/-) mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh(+/-) mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh(-/-) mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh(-/-) mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh(-/-) mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs.
Animals↗
A requirement for memory retrieval during and after long-term extinction learning.
Current learning theories are based on the idea that learning is driven by the difference between expectations and experience (the delta rule). In extinction, one learns that certain expectations no longer apply. Here, we test the potential validity of the delta rule by manipulating memory retrieval (and thus expectations) during extinction learning. Adrenergic signaling is critical for the time-limited retrieval (but not acquisition or consolidation) of contextual fear. Using genetic and pharmacologic approaches to manipulate adrenergic signaling, we find that long-term extinction requires memory retrieval but not conditioned responding. Identical manipulations of the adrenergic system that do not affect memory retrieval do not alter extinction. The results provide substantial support for the delta rule of learning theory. In addition, the timing over which extinction is sensitive to adrenergic manipulation suggests a model whereby memory retrieval occurs during, and several hours after, extinction learning to consolidate long-term extinction memory.
Animals↗
Reduction of nerve growth factor receptor immunoreactivity in ischaemic gerbil hippocampal CA1 neurons after treatment with L-threo-3,4-dihydroxyphenylserine (DOPS).
Nerve growth factor (NGF) synthesis in cultured mouse L-M fibroblast and astroglial cells can be increased after the treatment with L-threo-3,4-dihydroxyphenylserine (DOPS). Since the increase of NGF is not blocked by the treatment with decarboxylase inhibitor, DOPS may have direct effect to increase the NGF content. NGF and its receptor (NGFR) are suggested to play an important role in the neuronal survival and regeneration under pathologic conditions. In this study, we studied a possible protective effect of DOPS against the hippocampal CA1 cell death after transient forebrain ischaemia in gerbils in relation to the change of NGFR immunoreactivity. We found that treatment with DOPS (300 mg kg-1) in combination with a decarboxylase inhibitor (benserazide, 10 mg kg-1) protected ischaemic hippocampal CA1 cell against delayed neuronal death (neuronal density = 125 +/- 24 mm-1) as compared to the treatment with vehicle (49 +/- 11 mm-1) (p < 0.01). The immunoreactivity for NGFR was scarcely present in the sham-control CA1 area but was induced from 1 h and markedly expressed at 7 days after recirculation in the vehicle group. However, it was slightly and transiently induced from 8 h to 2 days in the DOPS plus benserazide treated group. These data suggest that the protective role of DOPS on the ischaemic hippocampal CA1 cells may act through the NGF and its receptor system.
Animals↗
L-threo 3,4-dihydroxyphenylserine treatment during mouse perinatal and rat postnatal development does not alter the impact of dietary copper deficiency.
Dietary copper (Cu) deficiency was induced perinatally in Swiss Albino mice and postnatally in male Holtzman rats to investigate the effect of L-threo 3,4-dihydroxyphenylserine (DOPS) on pup survival and catecholamine levels in a 2 x 2 factorial design. Mouse dams were placed on one of four treatments 14 days after mating and rats at postnatal day 19 (P19). Treatments were Cu-adequate (Cu + ) and Cu-deficient (Cu - ) diets with or without DOPS (1 mg/ml) in the drinking water. Mouse pups were killed at P14 and rats at P49. Mortality in Cu - pups was 46% and not significantly improved by DOPS, 39%. A repeat study with mice adding ascorbic acid in the water with DOPS showed no improvement. Compared to Cu + animals, Cu - animals were smaller, anemic and had a 92% reduction in liver Cu. DOPS treatment made no improvement to and in some cases exacerbated the Cu deficiency. Catecholamine levels measured in heart and brain by LCEC showed decreased NE levels and increased DA levels in Cu - animals compared to controls. DOPS treatment did not alter this pattern. Although DOPS was present in treated animal's tissues, survival in mice and catecholamine levels in mice and rats were not altered by the 1 mg/ml dose of DOPS.
Animals↗
Treatment of dialysis-induced hypotension with L-threo-3,4-dihydroxyphenylserine.
L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline (norepinephrine), which is converted into noradrenaline when orally administered, was given orally to haemodialysed patients exhibiting dialysis-induced hypotension. In five patients given 300 mg L-DOPS plasma concentrations reached a peak of 1.43 +/- 0.59 micrograms/ml 6 h after administration and decreased slowly to disappear after 36 h. Plasma noradrenaline concentrations showed a significant increase (P < 0.05), reaching a peak of 1.28 +/- 0.64 ng/ml after 24 h and declined to 0.75 +/- 0.47 ng/ml by 48 h. Administration of L-DOPS to six patients during dialysis for 6 consecutive weeks showed no accumulation in the blood. Oral administration of 200-400 mg L-DOPS to 34 patients 1 h before dialysis prevented dialysis-induced hypotension and decreased the number of concurrent treatments required for hypotension. The signs and symptoms of hypotension were improved in 73.5% of the patients and persisted after dialysis in 64.7%. The preventive effect of L-DOPS was significantly more prominent in patients with predialysis systolic blood pressure less than 100 mmHg and in patients with non-diabetic nephropathy. L-DOPS appeared to be an effective and well-tolerated treatment for the prevention of dialysis-induced hypotension.
Administration, Oral↗
Sleeping with and without norepinephrine: effects of metoclopramide and D,L-threo-3,4-dihydroxyphenylserine on sleep in dopamine beta-hydroxylase deficiency.
Sleep characteristics are presented for two female patients (aged 21 and 31 years) with central and peripheral dopamine beta-hydroxylase (DBH) deficiency. This deficiency results in the absence of norepinephrine, epinephrine, and their metabolites in plasma, urine, and cerebrospinal fluid, while concentrations of dopamine are increased. The sleep pattern of these patients was studied when they were untreated, after blockade of central dopamine receptors with metoclopramide, and after restoring norepinephrine production with D,L-threo-3,4-dihydroxyphenylserine (DOPS). When the patients were untreated sleep duration was normal, with tendencies of a decreased amount of rapid eye movement (REM) sleep, presence of alpha-delta sleep, and an increased amount of slow-wave sleep. The amount of REM sleep varied between 18 and 21% of sleep period time. Administration of metoclopramide resulted in a slight reduction of REM sleep to 16-17%, whereas wakefulness after sleep onset increased. During treatment with DOPS, an increase in the amount of REM sleep was observed in both patients to an average amount of 27%. These data indicate that in patients with DBH deficiency norepinephrine is not essential for the development of a normal sleep/wake pattern but may have a facilitatory role in the generation of REM sleep.
Adult↗
Role of catecholamines in photoperiodically-induced gonadal development in Coturnix quail.
Explore the source record for details and available documents.
Animals↗
Suppression of hyperemia after brain ischemia by L-threo-3,4-dihydroxyphenylserine.
Although several studies have shown that L-threo3,4-dihydroxyphenylserine (DOPS) may provide a neuroprotective effect against ischemic brain damage, its protective mechanism is not fully understood. Glutamate release and hippocampal blood flow in ischemia with administration of DOPS were investigated to elucidate the neuroprotective mechanism of DOPS. Pre- (but not post-) ischemic administration of DOPS rescued 73% of hippocampal CA1 neurons (p < 0.001, compared with ischemia only) 1 week after transient global ischemia in gerbils. While glutamate release induced by ischemia was not affected, the increase of hippocampal blood flow during reperfusion was significantly suppressed by DOPS. These results demonstrate that DOPS may prevent reperfusion injury by suppression of hyperemia after ischemia, resulting in neuroprotection.
Animals↗