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. 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. Candicine occurs in a variety of plants, notably the cacti. 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. Candicine also occurs in several plants of genus Citrus. In the late 1950s, Japanese researchers isolated a toxic compound which they named 'maltoxin' from malted barley. 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. 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. 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. One of the earliest syntheses of candicine is that of Barger, who made candicine iodide by the N-methylation of hordenine, using methyl iodide. 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. 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.