Candicine

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Candicine
Candicine.svg
Names
Preferred IUPAC name
2-(4-Hydroxyphenyl)-N,N,N-trimethylethan-1-aminium
Other names
2-(4-Hydroxyphenyl)-N,N,N-trimethylethanaminium
Maltoxin
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
Properties
C11H18NO+,
HOC6H4(CH2)2N(CH3)3+
Molar mass 180.266205 Da (+ 126.90447, if iodide)
Appearancecolorless solid (chloride and iodide salts)
Melting point 234 °C (453 °F; 507 K)(iodide); 285 °C (decomposition of chloride)
Iodide and chloride are both highly soluble in water
Hazards
Main hazards Irritant
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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.

Contents

Occurrence

Candicine occurs in a variety of plants, notably the cacti. [1] This alkaloid was first isolated from the Argentinian cactus Trichocereus candicans (now reclassified as Echinopsis candicans), from which it derives its name, and from other Trichocereus species. T. candicans may contain up to 5% candicine, and is also a rich source of the closely related alkaloid hordenine. [2]

Candicine also occurs in several plants of genus Citrus . [3]

In the late 1950s, Japanese researchers isolated a toxic compound which they named "maltoxin" from malted barley. [4] After the publication of some papers on its pharmacology (see "Pharmacology" section), under this name, it was determined that maltoxin was identical to candicine, and the older name has been retained in subsequent articles. [5]

Candicine has also been found in the skin of the frog, Leptodactylus pentadactylus pentadactylus, at a concentration of 45 μg/g skin, but it is of much more limited occurrence amongst amphibians than its positional isomer, leptodactyline. [6] [7]

Chemistry

The dominant chemical characteristics of candicine are that it is a quaternary ammonium salt and a phenol. The quaternary ammonium cation is found in association with different anions, forming the corresponding salts, the commonest of which are the iodide and chloride, trivially named "candicine iodide" (or "hordenine methiodide") and "candicine chloride". Since it is impractical to isolate candicine from a natural source along with its original counterion(s), isolation procedures are designed so as to obtain it in association with a particular anion chosen by the investigator. The name "candicine" when used alone is thus not unequivocally chemically defined.

The presence of the phenolic group would make aqueous solutions of candicine salts weakly acidic, but no pKa seems to have been recorded. This phenolic group has been converted to the methyl ether by treatment of candicine with methyl iodide, to make O-methyl candicine iodide. [8]

Synthesis

One of the earliest syntheses of candicine is that of Barger, who made candicine iodide by the N-methylation of hordenine, using methyl iodide. [9] This method has become a standard one for the conversion of tertiary amines to quaternary salts. It was used again by Buck and co-workers, who also reported the conversion of candicine iodide to candicine chloride by treatment with AgCl. [10]

Pharmacology

The earliest pharmacological studies on candicine (under the name of hordenine methiodide) appear to be those of Barger and Dale, who studied its effects primarily in cats and isolated animal organ preparations. These researchers found candicine to closely resemble nicotine in its effects. For example, contractions of isolated sections of rabbit jejunum were produced by ~ 2 × 10−5M concentrations of the drug; 1 mg of candicine iodide given i.v. to cats produced the same rise in blood pressure as 0.5 mg nicotine; toxic doses produced respiratory paralysis. It was observed that in the same blood pressure assay, candicine iodide was about twice as potent as its structural analog tyramine, and much more potent than its even-closer analog, hordenine. [11]

After Reti's discovery (and naming) of candicine as a natural product, [12] a series of pharmacological investigations was carried out on this alkaloid by Luduena. These are summarized in Reti's review: as before, the similarity of effects between candicine and nicotine was noted. In Luduena's experiments, candicine first stimulated, then blocked ganglionic transmission; its effects were not altered by yohimbine, cocaine, or atropine, but completely counteracted by sparteine or tetrapropylammonium iodide. No muscarinic action was seen. Doses of 6 mg/kg were curare-like in the dog; similar effects were also observed in the toad, Bufo arenarum. [2]

Candicine [13] (as either the iodide or chloride) was re-investigated by Japanese pharmacologists in the early 1960s. Initial experiments on frogs, using rectus muscle and nerve-sartorius preparations from Rana nigromaculata nigromaculata, showed that the alkaloid caused contractions in the rectus at concentrations of 0.01–0.2 mg/mL, and blocked the response of the nerve-sartorius to direct or indirect electrical stimulation at similar concentrations. The contraction of the rectus was inhibited by pre-treatment with tubocurarine, as was the response of the nerve-sartorius (i.e., the normal muscle twitch was not reduced by the application of candicine subsequent to tubocurarine). The action of candicine in these assays was not affected by eserine. Taking additional observations into account, these researchers concluded that the effects on frog tissue of candicine most closely resembled those of the well-known depolarizing neuromuscular-blocking drug decamethonium. [14] An earlier comparison of 0.2 mg of candicine chloride with 2 mg of hordenine sulfate on the rectus muscle preparation showed that hordenine was much less potent at eliciting a contraction, even at 10× the concentration of candicine. [4]

Following their experiments on frogs, the Japanese group carried out a series of classical pharmacological investigations of candicine on cats and rabbits, and on various isolated animal organs/tissues. In rabbits, doses of 0.6 mg/kg, i.v., of candicine produced respiratory and cardiovascular disturbances lasting about 15 minutes. Body temperature was not affected; there was also mydriasis followed by miosis, and hypersalivation. In rabbits, i.v. doses of 2.1 mg/kg produced apnea, followed by death. In anesthetized cats, doses of 0.06–0.12 mg/kg, iv., also caused respiratory and cardiovascular disturbances: although the details were concentration-and time-dependent, the ultimate effects were ones of sustained respiratory stimulation and elevated blood pressure; the hypertension was not inhibited by atropine, but was antagonized by hexamethonium. Candicine caused contraction of the cat nictitating membrane. A concentration of 0.012 mg/mL applied to the isolated guinea pig atrium caused a decrease in the amplitude and rate of contractions, these effects being enhanced by eserine, but inhibited by atropine pre-treatment. Concentrations of 3-6 μg/mL produced contractions of the isolated guinea pig ileum which were inhibited by pre-treatment with atropine, hexamethonium, tubocurarine or cocaine, but were not affected by the presence of pyribenzamine or chlorpheniramine. Summarizing the results of these and other observations, the authors concluded that: candicine was primarily a stimulant of autonomic ganglia; it liberated catecholamines from the adrenal medulla; it showed muscarine-like and sympathomimetic effects in some assays, and it was a neuromuscular blocker of the depolarizing type. In many of these respects, candicine resembled nicotine and dimethylphenylpiperazinium (DMPP). [15]

Toxicology

LD50 = 10 mg/kg (mouse; s.c.); [16] LD50 = 36 mg/kg (mouse; i.p.); [15] LD50 = 50 mg/kg (rat). [2]

Effects on Plants

Candicine iodide has some plant growth-inhibiting properties: 50 μg/plant of the salt produced 76-100% inhibition of elongation of the second internode in beans, with indications of necrosis; ~ 100 μg of candicine iodide applied to the roots of sorghum seedlings caused a 50% inhibition in overall plant length. [17]

Effects on Brine Shrimp

The LC50 for candicine chloride in the brine shrimp bioassay is 923 μg/mL. [18]

See also

Related Research Articles

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.

Tyramine

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

Tetraethylammonium

Tetraethylammonium (TEA), (NEt+
4) or (Et4N+) is a quaternary ammonium cation consisting of four ethyl groups attached to a central nitrogen atom, and is positively charged. It is a counterion used in the research laboratory to prepare lipophilic salts of inorganic anions. It is used similarly to tetrabutylammonium, the difference being that its salts are less lipophilic and more easily crystallized.

Synephrine

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. p-Synephrine and m-synephrine are known for their longer acting adrenergic effects compared to norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange products, both of the "sweet" and "bitter" variety. The preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium. 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 (phenylephrine) is still used as a sympathomimetic, mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.

Tubocurarine chloride

Tubocurarine is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is now rarely used as an adjunct for clinical anesthesia because of safer alternatives, such as cisatracurium and rocuronium, are available.

Neuromuscular-blocking drug

Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

Lysergic acid hydroxyethylamide

D-Lysergic acid α-hydroxyethylamide, also known as D-lysergic acid methyl carbinolamide, is an alkaloid of the ergoline family, believed to be present in small amounts in various species in the Convolvulaceae (LSA), as well as some species of fungi.

Pralidoxime

Pralidoxime or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to treat organophosphate poisoning in conjunction with atropine and either diazepam or midazolam. It is a white solid.

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. Currently, 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.

Alcuronium chloride muscle relaxant

Alcuronium chloride is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuronium.

Methyllycaconitine

Methyllycaconitine (MLA) is a diterpenoid alkaloid found in many species of Delphinium (larkspurs). In common with many other diterpenoid alkaloids, it is toxic to animals, although the acute toxicity varies with species. Early research was focused on identifying, and characterizing the properties of methyllycaconitine as one of the principal toxins in larkspurs responsible for livestock poisoning in the mountain rangelands of North America. Methyllycaconitine has been explored as a possible therapeutic agent for the treatment of spastic paralyses in man, and it has been shown to have insecticidal properties. Most recently, it has become an important molecular probe for studying the pharmacology of the nicotinic acetylcholine receptor.

<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.

Tetraethylammonium bromide

Tetraethylammonium bromide (TEAB) is a quaternary ammonium compound with the chemical formula C8H20N+Br−, often written as "Et4N+Br−" in the chemical literature. It has been used as the source of tetraethylammonium ions in pharmacological and physiological studies, but is also used in organic chemical synthesis.

Deoxyepinephrine

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.

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.

Candocuronium iodide

Candocuronium iodide is an aminosteroid neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs. Its potential adjunctive use in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, but further development discontinued because of attendant cardiovascular effects, primarily tachycardia that was no worse than but also not an improvement over the clinically established pancuronium bromide. Candocuronium demonstrated a short duration and a rapid onset of action, with little or no ganglion blocking activity, and it was only slightly less potent than pancuronium.

<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.

Tetramethylammonium

Tetramethylammonium (TMA) or (Me4N+) is the simplest quaternary ammonium cation, consisting of four methyl groups attached to a central nitrogen atom, and is isoelectronic with neopentane. It is positively charged and can only be isolated in association with a counter-ion. Common salts include tetramethylammonium chloride and tetramethylammonium hydroxide. Tetramethylammonium salts are used in chemical synthesis and are widely employed in pharmacological research.

<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.

References

  1. ↑ T. A. Smith (1977). "Phenethylamines and related compounds in plants." Phytochemistry16 9-18.
  2. 1 2 3 L. Reti (1953). "β-Phenethylamines". In The Alkaloids, Vol. III, (R. H. F. Manske and H. L. Holmes, Eds.), pp. 313-338, New York: Academic Press.
  3. ↑ Servillo, Luigi; Giovane, Alfonso; D’Onofrio, Nunzia; Casale, Rosario; Cautela, Domenico; Ferrari, Giovanna; Balestrieri, Maria Luisa; Castaldo, Domenico (2014). "N-Methylated Derivatives of Tyramine in Citrus Genus Plants: Identification of N,N,N-Trimethyltyramine (Candicine)". Journal of Agricultural and Food Chemistry . 62 (12): 2679–2684. doi:10.1021/jf5001698. ISSN   0021-8561.
  4. 1 2 N. Urakawa et al. (1959). "Some chemical and pharmacological properties of an amine (maltoxin) isolated from malt rootlet." Jap. J. Pharmacol.9 41-45.
  5. ↑ N. Urukawa, Y. Hirabe and Y. Okubo (1961). "Identification of maltoxin, an active principle from malt rootlet, as candicine." Jap. J. Pharmacol.11 4-10.
  6. ↑ V. Erspamer, J. M. Cei and M. Roseghini (1963). "Occurrence of candicine (p-hydroxy phenylethyltrimethylammonium) in extracts of the skin of Leptodactylus pentadactylus pentadactylus." Life Sci.3 825-827.
  7. ↑ M. Roseghini et al. (1986). "Indole-, imidazole- and phenyl-alkylamines in the skin of one hundred and forty American amphibian species other than Bufonids." Comp. Biochem. Physiol. C85 139-147.
  8. ↑ K. W. Rosenmund (1910). "Die Synthese des Hordenins, eines Alkaloids aus Gerstenkeimen, und über (α)-p-Oxyphenyläthylamin." Chem. Ber.43 306-313.
  9. ↑ G. Barger (1909). "Synthesis of hordenine, the alkaloid from barley." J. Chem. Soc., Trans.95 2193-2197.
  10. ↑ J. S. Buck, R. Baltzly and W. S. Ide (1938). "β-Phenethylamine derivatives. Tertiary and quaternary salts." 60 1789-1792.
  11. ↑ G. Barger and H. H. Dale (1910). "Chemical structure and sympathomimetic action of amines." J. Physiol.41 19–59.
  12. ↑ L. Reti (1933) Compt. Rend. Soc. Biol.114 811.
  13. ↑ Referred to as "maltoxin" - see "Occurrence" section for explanation.
  14. ↑ N. Urakawa, T. Deguchi and Y. Ohkubo (1960). "Decamethonium-like action of maltoxin, an active principle from malt rootlet, on the frog muscle." Jap. J. Pharmacol.10 1-6.
  15. 1 2 T. Deguchi et al. (1963). "Ganglion stimulating action of candicine." Jap. J. Pharmacol.13 143–159.
  16. ↑ G. Habermehl (1969). "Chemie und Biochemie von Amphibiengiften." Naturwissenschaften56 615-622.
  17. ↑ N. B. Mandava, G. J. Kapadia and J. F. Worley (1981). "Inhibition of plant growth by phenethylamines and tetrahydroquinolines." J. Nat. Prod." 44 94-100.
  18. ↑ B. N. Meyer et al. (1983). "Cactus alkaloids. CIII. Coryphanthine and O-methyl-candicine, two new quaternary alkaloids from Coryphantha greenwoodii." J. Nat. Prod.46 688-693.
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