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. Methyllycaconitine was identified 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 paralysis, and it has been shown to have insecticidal properties. It has become an important molecular probe for studying the pharmacology of the nicotinic acetylcholine receptor.
Isolation MLA was first isolated from Delphinium brownii, Rydb. Presumably because he did not obtain the compound in sufficiently pure form, Manske declined to give it a name. The name "methyl-lycaconitine" was assigned by John Goodson, working at the Wellcome Chemical Research Laboratories in London, England, when he isolated the alkaloid, in purer form, from seeds of Delphinium elatum, L. in 1943. A more modern isolation procedure is described by Pelletier and his co-workers, who used seeds of the "garden larkspur", Consolida ambigua (also referred to as Delphinium ajacis) as their plant source.
Structure determination The complete molecular structure for MLA, correct in all but one detail, was first published by Kuzovkov and Platonova in 1959. This structure, supported in part by X-ray crystallography (considered usually to be a "definitive" analytical technique) of a chemical derivative of MLA performed by Maria Przybylska, was accepted as correct until the early 1980s. The stereochemistry of the methoxy group at C-1 from the β- to α- configuration has been determined. Thus any drawing of MLA appearing before Pelletier's 1981 paper will show the structure with the incorrect stereochemistry at C-1.
Chemistry
Synonyms [1α,4(S),6β,14α,16β]-20-Ethyl-1,6,14,16-tetramethoxy-4-[[[2-(3-methyl-2,5-dioxo-1-pyrrolidinyl)benzoyl]oxy]methyl]aconitane-7,8-diol; also referred to, incorrectly, as "N-methyl lycaconitine" in a few publications.
Physico-chemical properties MLA is soluble in chloroform, but does not dissolve well in water. The free base of MLA has not been obtained in crystalline form, and in its amorphous form it melts ultimately at 128 °C; the hydriodide salt has a melting point of 201 °C.; the perchlorate salt melts at 195 °C The citrate salt is the most common form in which MLA is currently available commercially. A pKa does not seem to have been recorded for MLA, but it is considered to be a weak base because it can be readily extracted into diethyl ether from an aqueous solution at pH 7.5-8. The optical rotation of the free base, [α]D was found to be +49° in alcohol.
Molecular structure Although commonly referred to as a "diterpenoid" alkaloid, MLA is, strictly speaking, a nor-diterpenoid, since its carbon skeleton only contains 19 C atoms, one having been deleted somewhere during its biosynthesis. Otherwise, the MLA molecule comprises a tertiary amine, two tertiary alcohols, four methyl ether groups, and a complex ester based on anthranilic acid and methylsuccinic acid. This N-(2-carboxyphenyl)-methylsuccinamido-ester is quite rare amongst natural products.
Synthesis As of April, 2012 no total synthesis of MLA has been reported. A semi-synthesis of MLA, starting from its "parent" amino-alcohol, lycoctonine (obtained by simple alkaline hydrolysis of natural MLA ) was reported in 1994.
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