Deoxyepinephrine
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Deoxyepinephrine, also known by the common names ''N''-methyldopamine and epinine, is an
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
and
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
that is structurally related to the important
neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
. All three of these compounds also belong to the
catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a subst ...
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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
ibopamine, which has been used to treat
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
.


Occurrence

Epinine does not seem to occur widely, but it is present as a minor alkaloid in some plants, such as the
peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. ''Peyote'' is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to gl ...
cactus, ''
Lophophora williamsii The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. ''Peyote'' is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to gl ...
'', and a species of ''
Acacia ''Acacia'', commonly known as the wattles or acacias, is a large genus of shrubs and trees in the subfamily Mimosoideae of the pea family Fabaceae. Initially, it comprised a group of plant species native to Africa and Australasia. The genus na ...
'', as well as in
Scotch Broom ''Cytisus scoparius'' ( syn. ''Sarothamnus scoparius''), the common broom or Scotch broom, is a deciduous leguminous shrub native to western and central Europe. In Britain and Ireland, the standard name is broom; this name is also used for other ...
, ''
Cytisus scoparius ''Cytisus scoparius'' ( syn. ''Sarothamnus scoparius''), the common broom or Scotch broom, is a deciduous leguminous shrub native to western and central Europe. In Britain and Ireland, the standard name is broom; this name is also used for oth ...
''. This compound has also been isolated from the
adrenal medulla The adrenal medulla ( la, medulla glandulae suprarenalis) is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cel ...
of pigs and cows, and from the
toad Toad is a common name for certain frogs, especially of the family Bufonidae, that are characterized by dry, leathery skin, short legs, and large bumps covering the parotoid glands. A distinction between frogs and toads is not made in scientif ...
, ''
Bufo marinus The cane toad (''Rhinella marina''), also known as the giant neotropical toad or marine toad, is a large, terrestrial true toad native to South and mainland Central America, but which has been introduced to various islands throughout Oceania ...
''. It has also been detected in the
locust Locusts (derived from the Vulgar Latin ''locusta'', meaning grasshopper) are various species of short-horned grasshoppers in the family Acrididae that have a swarming phase. These insects are usually solitary, but under certain circumstanc ...
, ''
Locusta migratoria The migratory locust (''Locusta migratoria'') is the most widespread locust species, and the only species in the genus ''Locusta''. It occurs throughout Africa, Asia, Australia and New Zealand. It used to be common in Europe but has now become ...
''.


Chemistry


Preparation

The first total synthesis of epinine was reported by Buck, who prepared it from
3,4-dimethoxyphenethylamine 3,4- Dimethoxy phenethylamine (DMPEA) is a chemical compound of the phenethylamine class. It is an analogue of the major human neurotransmitter dopamine where the 3- and 4-position hydroxy groups have been replaced with methoxy groups. It is ...
("homoveratrylamine") by first converting the latter to its
Schiff base In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...
with
benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. It is a colorless liquid with a characteristic almond-like odor. ...
, then ''N''-methylating this with
methyl iodide Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one h ...
; hydrolysis of the resulting product was followed by cleavage of the methyl ethers using
hydriodic acid Hydroiodic acid (or hydriodic acid) is an aqueous solution of hydrogen iodide (HI). It is a strong acid, one that is ionized completely in an aqueous solution. It is colorless. Concentrated solutions are usually 48% to 57% HI. Reactions Hydr ...
to furnish epinine.J. S. Buck (1930). "Synthesis of lodal and epinine." ''J. Am. Chem. Soc.'' 52 4119-4122. A very similar synthesis, differing only in the use of
dimethyl sulfate Dimethyl sulfate (DMS) is a chemical compound with formula (CH3O)2SO2. As the diester of methanol and sulfuric acid, its formula is often written as ( CH3)2 SO4 or Me2SO4, where CH3 or Me is methyl. Me2SO4 is mainly used as a methylating agent ...
for the ''N''-methylation, and HBr for the ''O''-demethylation, but providing more extensive experimental details, was published by Borgman in 1973.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. An earlier semi-synthesis (so-called because it began with the natural product
laudanosine Laudanosine or ''N''-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however suc ...
) due to PymanF. 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. is incorrectly cited by Buck, and the error carried over to the entry for epinine (under the name deoxyepinephrine) in the Merck Index. Common salts of epinine are: hydrochloride, C9H13NO2.HCl, m.p. 179-180 °C; sulfate, (C9H13NO2)2.H2SO4, m.p. 289-290 °C; hydrobromide, C9H13NO2.HBr, m.p. 165-166 °C.


Structure

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


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 An antihypotensive agent, also known as a vasopressor agent or simply vasopressor, or pressor, is any substance, whether endogenous or a medication, that tends to raise low blood pressure. Some antihypotensive drugs act as vasoconstrictors to inc ...
potency of epinephrine, but about 5 x the potency of dopamine ("amino-ethyl-catechol") in cat preparations. 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.M. L. Tainter (1930). "Comparative actions of sympathomimetic compounds: catechol derivatives." ''J. Pharmacol. Exp. Ther.'' 40 43-64. Tainter further quantified the pressor activity of epinine in
atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...
-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. Eventually, epinine was determined to be a non-selective stimulant of dopamine (DA) receptors, α-, and β-
adrenoceptors 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 ...
, with the stimulation of D2 receptors leading to inhibition of
noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
and
ganglionic A ganglion is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system there are both sympatheti ...
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. Comparable studies, in which blood pressure, heart rate and serum
prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
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. 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 Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pro ...
and
natriuresis Natriuresis is the process of sodium excretion in the urine through the action of the kidneys. It is promoted by ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldosterone. Natriuresis lowers t ...
- 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 Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
release.


Toxicity

LD50 for HCl salt: 212 mg/kg (mouse; i.p.). For comparison, it might be noted that
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
has a LD50 of 1978 mg/kg under the same conditions.J. Z. Ginos et al. (1975). "Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines." 18 1194-1200.


See also

*
Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
* N,N-Dimethyldopamine *
N-Methyltyramine ''N''-Methyltyramine (NMT), also known as 4-hydroxy-''N''-methylphenethylamine, is a human trace amine and natural substituted phenethylamine, phenethylamine alkaloid found in a variety of plants.T. A. Smith (1977). "Phenethylamine and related c ...


References

{{Phenethylamines Alpha-1 adrenergic receptor agonists Alpha-2 adrenergic receptor agonists Beta-adrenergic agonists Catecholamines D1-receptor agonists D2-receptor agonists Dopamine agonists Norepinephrine-dopamine releasing agents