Deoxyepinephrine

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Deoxyepinephrine
Deoxyepinephrine2DCSD.svg
Names
Preferred IUPAC name
4-[2-(Methylamino)ethyl]benzene-1,2-diol
Other names
Epinine; N-Methyldopamine
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.007.200 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Deoxyepinephrine
PubChem CID
UNII
  • InChI=1S/C9H13NO2/c1-10-5-4-7-2-3-8(11)9(12)6-7/h2-3,6,10-12H,4-5H2,1H3 Yes check.svgY
    Key: NGKZFDYBISXGGS-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C9H13NO2/c1-10-5-4-7-2-3-8(11)9(12)6-7/h2-3,6,10-12H,4-5H2,1H3
    Key: NGKZFDYBISXGGS-UHFFFAOYAT
  • Oc1ccc(cc1O)CCNC
Properties
C9H13NO2
Molar mass 167.21 g/mol
Appearancecolorless crystalline solid
Melting point 188 to 189 °C (370 to 372 °F; 461 to 462 K) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)
Infobox references

Deoxyepinephrine, also known by the common names N-methyldopamine and epinine, is an organic compound and natural product that is structurally related to the important neurotransmitters dopamine and epinephrine. All three of these compounds also belong to the catecholamine family. The pharmacology of epinine largely resembles that of its "parent", dopamine. Epinine has been found in plants, insects and animals. It is also of significance as the active metabolic breakdown product of the prodrug ibopamine, which has been used to treat congestive heart failure. [2] [3]

Contents

Occurrence

Epinine does not seem to occur widely, but it is present as a minor alkaloid in some plants, such as the peyote cactus, Lophophora williamsii , [4] and a species of Acacia , [5] as well as in Scotch Broom, Cytisus scoparius . [6] This compound has also been isolated from the adrenal medulla of pigs and cows, [7] and from the toad, Bufo marinus . [8] It has also been detected in the locust, Locusta migratoria . [9]

Chemistry

Preparation

The first total synthesis of epinine was reported by Buck, who prepared it from 3,4-dimethoxyphenethylamine ("homoveratrylamine") by first converting the latter to its Schiff base with benzaldehyde, then N-methylating this with methyl iodide; hydrolysis of the resulting product was followed by cleavage of the methyl ethers using hydriodic acid to furnish epinine. [10] A very similar synthesis, differing only in the use of dimethyl sulfate for the N-methylation, and HBr for the O-demethylation, but providing more extensive experimental details, was published by Borgman in 1973. [11]

An earlier semi-synthesis (so-called because it began with the natural product laudanosine) due to Pyman [1] is incorrectly cited by Buck, [10] and the error carried over to the entry for epinine (under the name deoxyepinephrine) in the Merck Index. [12]

Common salts of epinine are: hydrochloride, C9H13NO2.HCl, m.p. 179-180 °C; sulfate, (C9H13NO2)2.H2SO4, m.p. 289-290 °C; [1] hydrobromide, C9H13NO2.HBr, m.p. 165-166 °C. [11]

Structure

The X-ray structure of epinine hydrobromide has been reported. [13]

Pharmacology

One of the most prominent pharmacological characteristics of epinine, its ability to raise blood pressure, was noted as early as 1910, by Barger and Dale, who reported that "methylamino-ethyl-catechol", as they called it, had about 1/7 x the pressor potency of epinephrine, but about 5 x the potency of dopamine ("amino-ethyl-catechol") in cat preparations. [14] The Buroughs Wellcome Co., for which Barger, Dale and Pyman (see "Chemistry" section) worked, subsequently marketed the hydrochloride salt of "methylamino-ethyl-catechol", under the name "epinine", as a substitute for epinephrine. [15] Tainter further quantified the pressor activity of epinine in atropine-treated and anesthetized intact cats, showing that doses of 0.02-0.2 mg, given i.v., were about 1/12 as active as l-epinephrine, but that the effect lasted about twice as long (~ 3 minutes), and was accompanied by an increase in pulse rate. [15]

Eventually, epinine was determined to be a non-selective stimulant of dopamine (DA) receptors, α-, and β-adrenoceptors, with the stimulation of D2 receptors leading to inhibition of noradrenergic and ganglionic neurotransmission. These studies, conducted using anesthetized animals, were amplified by van Woerkens and co-workers, who compared the effects of epinine and dopamine in unanesthetized pigs, so as to avoid any possible influences of an anesthetic. Drug doses were in the range of 1-10 μg/kg/min, administered by i.v. infusion over a period of 10 minutes. The results of these experiments showed that, in pigs, over the dose-range employed, epinine was more potent than dopamine as an agonist on D2, α-, and β2-receptors, but was weaker than dopamine as a D1-agonist. The β1-agonist effect of both compounds was weak or non-existent. [16]

Comparable studies, in which blood pressure, heart rate and serum prolactin levels were measured after the administration of 0.5-4 μg/kg/min of epinine by i.v. infusion over a 15-minute period to healthy humans, were reported subsequently by Daul and co-workers. [17] These investigators found that at lower doses (0.5 or 1.0 μg/kg/min), which produced plasma concentrations of 20-80 nM/L, epinine, in common with dopamine, caused a fall in prolactin level, but did not affect blood pressure or heart rate. At higher doses (2.0 or 4.0 μg/kg/min), epinine significantly increased both systolic and diastolic blood pressure, as well as heart rate. In contrast, dopamine caused an increase in systolic blood pressure and heart rate only. Both drugs increased diuresis and natriuresis - effects that are thought to be due to the activation of renal D1 receptors. It was concluded that at the lower doses, epinine and dopamine exerted their effects only at DA (D2) receptors, but did not activate α- or β-adrenoceptors. At the higher doses, epinine activated α-, β1- and β2-receptors to about the same extent, whereas dopamine showed only a mild stimulation of β1-receptors, without any effects on α- or β2-receptors. Additionally, it was observed that the effects of epinine were largely due to its direct action on receptors, while dopamine also produced some of its effects indirectly, by stimulating norepinephrine release.

Toxicity

LD50 for HCl salt: 212 mg/kg (mouse; i.p.). For comparison, it might be noted that dopamine has a LD50 of 1978 mg/kg under the same conditions. [18]

See also

Related Research Articles

Catecholamine Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

Adrenergic receptor Class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline)

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, β2 agonists and α2 agonists, which are used to treat high blood pressure and asthma, for example.

Phenethylamine

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

Sympathomimetic drug

Sympathomimetic drugs are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. The primary endogenous agonists of the sympathetic nervous system are the catecholamines, which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3, although there are more subtypes, and agonists vary in specificity between these receptors, and may be classified respectively. However, there are also other mechanisms of adrenergic agonism. Epinephrine and norepinephrine are endogenous and broad-spectrum. More selective agonists are more useful in pharmacology.

Epibatidine

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

AMPT

Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulated through the phosphorylation of different serine residues in regulatory domain sites. Catecholamine biosynthesis starts with dietary tyrosine, which is hydroxylated by tyrosine hydroxylase and it is hypothesized that AMPT competes with tyrosine at the tyrosine-binding site, causing inhibition of tyrosine hydroxylase.

Hordenine

Hordenine (N,N-dimethyltyramine) is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley. Chemically, hordenine is the N-methyl derivative of N-methyltyramine, and the N,N-dimethyl derivative of the well-known biogenic amine tyramine, from which it is biosynthetically derived and with which it shares some pharmacological properties. As of September 2012, hordenine is widely sold as an ingredient of nutritional supplements, with the claims that it is a stimulant of the central nervous system, and has the ability to promote weight loss by enhancing metabolism. In experimental animals, given sufficiently large doses parenterally, hordenine does produce an increase in blood pressure, as well as other disturbances of the cardiovascular, respiratory, and nervous systems. These effects are generally not reproduced by oral administration of the drug in test animals, and virtually no scientific reports of the effects of hordenine in human beings have been published.

Ibopamine

Ibopamine is a sympathomimetic drug, designed as a prodrug of epinine, used in ophthalmology. It induces mydriasis. It also has been investigated for use in the treatment of congestive heart failure.

<i>N</i>-Methylphenethylamine

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate. PEA and NMPEA are both alkaloids that are found in a number of different plant species as well. Some Acacia species, such as A. rigidula, contain remarkably high levels of NMPEA. NMPEA is also present at low concentrations in a wide range of foodstuffs.

Adrenaline Hormone and medication

Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions. Adrenaline is normally produced both by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an important role in the fight-or-flight response by increasing blood flow to muscles, output of the heart by acting on SA Node, pupil dilation response and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals and some single-celled organisms. Polish physiologist Napoleon Cybulski first isolated adrenaline in 1895.

Phenylethanolamine

Phenylethanolamine, or β-hydroxyphenethylamine, is a trace amine with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. As an organic compound, phenylethanolamine is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs in the substituted phenethylamine class. In common with these compounds, phenylethanolamine has strong cardiovascular activity and, under the name Apophedrin, has been used as a drug to produce topical vasoconstriction.

<i>N</i>-Methyltyramine

N-Methyltyramine (NMT), also known as 4-hydroxy-N-methylphenethylamine, is a human trace amine and natural phenethylamine alkaloid found in a variety of plants. As the name implies, it is the N-methyl analog of tyramine, which is a well-known biogenic trace amine with which NMT shares many pharmacological properties. Biosynthetically, NMT is produced by the N-methylation of tyramine via the action of the enzyme phenylethanolamine N-methyltransferase in humans and tyramine N-methyltransferase in plants.

Candicine

Candicine is a naturally occurring organic compound that is a quaternary ammonium salt with a phenethylamine skeleton. It is the N,N,N-trimethyl derivative of the well-known biogenic amine tyramine, and, being a natural product with a positively charged nitrogen atom in its molecular structure, it is classed as an alkaloid. Although it is found in a variety of plants, including barley, its properties have not been extensively studied with modern techniques. Candicine is toxic after parenteral administration, producing symptoms of neuromuscular blockade; further details are given in the "Pharmacology" section below.

<i>N</i>,<i>N</i>-Dimethyldopamine

N,N-Dimethyldopamine (DMDA) is an organic compound belonging to the phenethylamine family. It is related structurally to the alkaloid epinine (N-methyldopamine) and to the major neurotransmitter dopamine. Because of its structural relationship to dopamine, DMDA has been the subject of a number of pharmacological investigations. DMDA has been detected in Acacia rigidula.

Halostachine alkaloid

Halostachine is a natural product, an alkaloid first isolated from the Asian shrub Halostachys caspica, and structurally a β-hydroxy-phenethylamine related to its better-known "parent" biogenic amine, phenylethanolamine, to the adrenergic drug synephrine, and to the alkaloid ephedrine. The pharmacological properties of halostachine have some similarity to those of these structurally-related compounds, and Halostachys caspica extracts have been included as a constituent of certain OTC dietary supplements, but halostachine has never been developed as a prescription drug. Although it is found in nature as a single stereoisomer, halostachine is more commonly available as a synthetic product in the form of its racemate. In appearance it is a colorless solid.

History of catecholamine research

The catecholamines comprise the endogenous substances dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) as well as numerous artificially synthesized compounds such as isoprenaline. Their investigation constitutes a prominent chapter in the history of physiology, biochemistry and pharmacology. Adrenaline was the first hormone extracted from its endocrine gland and obtained in pure form, before the word hormone was coined. It was also the first hormone the structure and biosynthesis of which were clarified. Apart from acetylcholine, adrenaline and noradrenaline were the first neurotransmitters to be discovered and the first intercellular biochemical signals to be found in intracellular vesicles. The β-adrenoceptor was the first G protein-coupled receptor the gene of which was cloned. Goal-directed catecholamine research began with the preparation by George Oliver and Edward Albert Sharpey-Schafer of a pharmacologically active extract from the adrenal glands.

β2-adrenoceptor agonists is a group of drugs that act selectively on β2-receptors in the lungs causing bronchodilation. β2-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the non-selective beta-agonist isoprenaline was used. The aim of the drug development through the years has been to minimise side effects, achieve selectivity and longer duration of action. The mechanism of action is well understood and has facilitated the development. The structure of the binding site and the nature of the binding is also well known, as is the structure activity relationship.

Dopamine (medication)

Dopamine, sold under the brandname Intropin among others, is a medication most commonly used in the treatment of very low blood pressure, a slow heart rate that is causing symptoms, and, if epinephrine is not available, cardiac arrest. In newborn babies it continues to be the preferred treatment for very low blood pressure. In children epinephrine or norepinephrine is generally preferred while in adults norepinephrine is generally preferred for very low blood pressure. It is given intravenously or intraosseously as a continuous infusion. Effects typically begin within five minutes. Doses are then increased to effect.

2-Hydroxyestradiol

2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol.

References

  1. 1 2 3 F. L. Pyman (1910). "XXVIII. Isoquinoline derivatives. Part III. o-Dihydroxy-bases. The conversion of 1-keto-6,7-dimethoxy-2-methyltetrahydroisoquinolines into 3:4-dihydroxyphenylethylalkylamines." J. Chem. Soc., Trans.97 264-280.
  2. ↑ P. A. Zwieten (1994). "Pharmacotherapy of congestive heart failure." Pharmacy World & Science16 334 - 342.
  3. ↑ R. Gifford, W. C. Randolph, F. C. Heineman and J. A. Ziemniak (1986). "Analysis of epinine and its metabolites in man after oral administration of its pro-drug ibopamine using high-performance liquid chromatography with electrochemical detection." Journal of Chromatography B381 83-93. doi 10.1016/S0378-4347(00)83567-7
  4. ↑ J. Lundstrom (1971). "Biosynthesis of mescaline and tetrahydroisoquinoline alkaloids in Lophophora williamsii (Lem.) Coult. Occurrence and biosynthesis of catecholamine and other intermediates." Acta Chem. Scand.25 3489-3499. http://actachemscand.dk/pdf/acta_vol_25_p3489-3499.pdf
  5. ↑ B. A. Clement, C. M. Goff and T. D. A. Forbes (1998). "Toxic amines and alkaloids from Acacia rigidula." Phytochemistry49 1377-1380.
  6. ↑ T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochemistry16 9-18.
  7. ↑ P. Laduron, P. van Gompel, J. Leysen and M. Claeys (1974). " In vivo formation of epinine in adrenal medulla. A possible step for adrenaline biosynthesis." Naunyn-Schmiedebergs Arch. Pharmacol.286 227-238.
  8. ↑ F. Märki, J. Axelrod and B. Witkop (1962). "Catecholamines and N-methyltransferase in the South American toad (Bufo marinus)." Biochim. Biophys. Acta58 367-369.
  9. ↑ S. Tanaka and N. Takeda (1997). "Biogenic monoamines in the brain and the corpus cardiacum between albino and normal strains of the migratory locust, Locusta migratoria." Comp. Biochem. Physiol. Pt. C: Comp. Pharmacol. Toxicol.117 221-227.
  10. 1 2 J. S. Buck (1930). "Synthesis of lodal and epinine." J. Am. Chem. Soc.52 4119-4122.
  11. 1 2 R. Borgman et al. (1973). "Synthesis and pharmacology of centrally acting dopamine derivatives and analogs in relation to Parkinson's Disease." J. Med. Chem.16 630-633.
  12. ↑ The Merck Index, 15th Ed. (2013), p. 524 Monograph 2904, O'Neil: The Royal Society of Chemistry. Available online at: http://www.rsc.org/Merck-Index/monograph/mono1500002904
  13. ↑ J. Giesecke (1976). "The structure of the catecholamines. V. The crystal and molecular structure of epinine hydrobromide." Acta Crystallographica Section B32 2337-2340.
  14. ↑ G. Barger and H. H. Dale (1910)."Chemical structure and sympathomimetic action of amines." J. Physiol.41 19-59.
  15. 1 2 M. L. Tainter (1930). "Comparative actions of sympathomimetic compounds: catechol derivatives." J. Pharmacol. Exp. Ther.40 43-64.
  16. ↑ L. J. van Woerkens, F. Boomsma, A. J. Man in 't Veld, M. M. Bevers, P. D. Verdouw (1992). "Differential cardiovascular and neuroendocrine effects of epinine and dopamine in conscious pigs before and after adrenoceptor blockade." Br. J. Pharmacol.107 303–310.
  17. ↑ A. Daul et al. (1995). "Dose-dependent separation of dopaminergic and adrenergic effects of epinine in healthy volunteers." Naunyn-Schmiedebergs Arch. Pharmacol.352 429-437
  18. ↑ J. Z. Ginos et al. (1975). "Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines." 18 1194-1200.
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