SynephrineSynephrineor, more specifically, p -synephrineis oxedrine high alkaloidoccurring sustanon 250 mg kaufen in some plants and animals, and also in approved drugs products as its m -substituted analog known as neo-synephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange Citrus species products, both of the "sweet" and "bitter" variety. Extracts of oxedrine high same material or purified synephrine are also marketed in the US, sometimes in combination with caffeineas a weight-loss-promoting oxedrine high supplement for oral consumption. While the traditional preparations have been in use oxedrine high millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, m -synephrine is still used as a sympathomimetic i.
Synephrine - Wikipedia
Synephrine , or, more specifically, p -synephrine , is an alkaloid , occurring naturally in some plants and animals, and also in approved drugs products as its m -substituted analog known as neo-synephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange Citrus species products, both of the "sweet" and "bitter" variety.
Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine , as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, m -synephrine is still used as a sympathomimetic i.
Mixtures containing synephrine as only one of their chemical components regardless of whether these are of synthetic or natural origin should not be assumed to produce exactly the same biological effects as synephrine alone. In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a phenethylamine skeleton, and is related to those of many other drugs, and to the major neurotransmitters epinephrine and norepinephrine.
Synephrine, although already known as a synthetic organic compound , was first isolated as a natural product from the leaves of various Citrus trees, and its presence noted in different Citrus juices, by Stewart and co-workers in the early s. However, this compound is found predominantly in a number of Citrus species, including "bitter" and "sweet" orange varieties. Extracts of unripe fruit from Asian cultivars of Citrus aurantium commonly known as "bitter" orange , collected in China, were reported to contain synephrine levels of about 0.
An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.
A sample of commercial Japanese C. An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results: Marrs sweet orange C.
No synephrine was detected in: Rio Red grapefruit C. Numerous additional comparable analyses of the synephrine content of Citrus fruits and products derived from them may be found in the research literature. Low levels of synephrine have been found in normal human urine,   as well as in other mammalian tissue. A recent study of synephrine in human blood platelets by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine 0.
Since synephrine exists as either of two enantiomers see Chemistry section below for further discussion , which do not produce identical biological effects see Pharmacology section below some researchers have examined the stereoisomeric composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those Citrus species which have been studied predominantly as the l-isomer,   low levels of d-synephrine have been detected in juice and marmalade made from C.
The biosynthesis of synephrine in Citrus species is believed to follow the pathway: Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of Citrus aurantium "bitter orange" , bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical i.
As a synthetic drug, synephrine first appeared in Europe in the late s, under the name of Sympatol. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala. There is no mention of synephrine in editions of Drill's Pharmacology in Medicine later than the 3rd, nor is there any reference to synephrine in the Physicians' Desk Reference , nor in the current FDA "Orange Book".
There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names m-synephrine , Meta-synephrine and Neosynephrine , all of which refer to a related drug and naturally-occurring amine more commonly known as phenylephrine.
Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including Sympatol , Sympathol , Synthenate , and oxedrine , while phenylephrine has also been called m-Sympatol.
The synephrine with which this article deals is sometimes referred to as p-synephrine in order to distinguish it from its positional isomers, m -synephrine and o -synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry see Chembox, at right. Confusion over the distinctions between p - and m -synephrine has even contaminated the primary research literature.
The only completely unambiguous names for synephrine are: In terms of molecular structure, synephrine has a phenethylamine skeleton, with a phenolic hydroxy - group, an alcoholic hydroxy- group, and an N -methylated amino -group. Alternatively, synephrine might be described as a phenylethanolamine with an N -methyl and p -hydroxy substituent.
The amino-group confers basic properties on the molecule, whereas the phenolic —OH group is weakly acidic: Common salts of racemic synephrine are its hydrochloride , C 9 H 13 NO 2. The presence of the hydroxy-group on the benzylic C of the synephrine molecule creates a chiral center , so the compound exists in the form of two enantiomers , d- and l- synephrine, or as the racemic mixture , d,l- synephrine.
The dextrorotatory d-isomer corresponds to the S -configuration , and the levorotatory l-isomer to the R -configuration. Racemic synephrine has been resolved using ammonium 3-bromo-camphorsulfonate. The X-ray structure for synephrine has been determined. Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO 2 , ultimately yielding the p -benzyloxy-phenyloxazolidone.
This was N -methylated using dimethyl sulfate , then hydrolyzed and O -debenzylated by heating with HCl, to give racemic synephrine. Much reference has been made in the literature both lay and professional of the structural kinship of synephrine with ephedrine , or with phenylephrine , often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties.
However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate. If the synephrine phenolic 4-OH group is shifted to the meta -, or 3-position on the benzene ring, the compound known as phenylephrine or m -synephrine, or "Neo-synephrine" results; if the same group is shifted to the ortho -, or 2-position on the ring, o -synephrine results.
Four stereoisomers two pairs of enantiomers are possible for this substance. The above structural relationships all involve a change at one position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at two different positions: Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.
The main differences of the synephrine isomers compared for example to the ephedrines are the hydroxy-substitutions on the benzene ring. Synephrines are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics. One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs.
Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels.
There is now ample evidence that synephrine produces most of its biological effects by acting as an agonist i. However, the potency of synephrine at these receptors is relatively low i. There is some evidence that synephrine also has weak activity at 5-HT receptors , and that it interacts with TAAR1 trace amine-associated receptor 1. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers. Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synopsis.
Pharmacological studies on synephrine date back to the late s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals.
Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal bronchi , in situ , even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of histamine was not reversed by either l-synephrine or d,l-synephrine. In experiments with isolated sheep carotid artery, d-, l- and d,l-synephrine all showed some vasoconstrictor activity: Qualitatively similar results were obtained in a rabbit ear preparation: Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1: Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of mustard oil into the eyes of rabbits.
Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in blood sugar. In experiments on anesthetized cats, Papp and Szekeres found that synephrine stereochemistry unspecified raised the thresholds for auricular and ventricular fibrillation , an indication of anti-arrhythmic properties. Evidence that synephrine might have some central effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models [i] of anti-depressant activity.
This characteristic immobility could be counteracted by the pre-administration of prazosin. In mice pre-treated with reserpine , [l] an oral dose of 0. This enhanced release by l-synephrine was blocked by nisoxetine.
In the rabbit saphenous assay, the pD 2 of l-synephrine was 4. The potency, expressed in terms of pD 2 of synephrine in these species was as follows: The binding of racemic synephrine to cloned human adrenergic receptors has been examined: A number of studies of the effects of synephrine in humans, most of them focusing on its cardio-vascular properties, have been performed since its introduction as a synthetic drug around Respiration was generally not affected during these experiments.
There are a number of studies, references to many of which may be found in the review by Stohs and co-workers. The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.
Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in glutathione GSH concentration, and in the activity of glutathione peroxidase GPx.
Information about the safety and efficacy of synephrine used as a single drug may be deduced from the foregoing review of the literature in this Article. This information is, by and large, not contended.
In insects, synephrine has been found to be a very potent agonist at many invertebrate octopamine receptor preparations, and is even more potent than octopamine at a locust Schistocerca americana gregaria nerve-muscle preparation.
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