LYCORINE

Lycoris radiate, a traditional Chinese medicine (TCM), is the bulb of the amaryllidaceous Lycoris radiata herb. It has been applied for clinical purposes for centuries. It is firstly recorded in Tujing Bencao and mainly used for the pyogenic infections. According to A Supplement to Compendium of Materia Medica, lycoris radiate may be used for treating acute throat trouble, phlegm node, baihuodan, and pulmonary abscess.
There are about 20 Lycoris species in the world, which are widely distributed in China and Japan. Lycoris radiate is an amazing horticultural plant with a graceful shape and a bright color. In TCM, it is acrid in taste and neutral in nature, with functions of detoxication, easy expectoration, and diuresis and emesis promotion. According to the modern medicine, lycoris radiate is considered to be in favor of the central nervous system and cardiovascular system.
The main active ingredients extracted from the lycoris herbs are about 40 alkaloids with various contents. Pharmacological tests indicate that galanthamine, lycorine, lycoramine, lycorenine, and crinine are the major effective medicinal ingredients. Lycorine may be used to treat amebic dysentery and against cancer. Moreover, galanthamine, dihydrogalanthamine, and lycoramine may be used to treat infantile paralysis and restore nerve functions and against traumatic paraplegia, etc. Lycoris radiate is famous because galanthamine has been approved by FDA as an anti-Alzheimer disease drug. Lycoris radiate is the only natural source for galanthamine with extremely low content (<0.02%).

Large prismatic crystals. Melting point 275-280°C (decomposition). Soluble in dilute acid, insoluble in alcohol, chloroform and petroleum ether, almost water soluble in water and alkalis, alkaline reaction to litmus. Its hydrochloride is long needle-like crystals, melting point 217 ° C (decomposition), with a molecule of water of crystallization of stilbene hydrochloride melting point of 206 ° C.. Soluble in 20 parts of water.

Appearance: colorless prismatic crystal. Solubility: insoluble in water; sparingly soluble in ethyl alcohol and diethyl ether. Melting point: 275–280°C (decomposition). Specific optical rotation: right-handed optical rotation with a specific optical rotation of 129° (98% ethyl alcohol).

In 1895, Morishima successfully extracted lycorine from the bulb of Lycoris radiata. However, its structure was unidentified until in 1935. In 1959, its stereochemical structure was dissected by monocrystal.
The solvent extraction method, chromatographic separation, and resin absorption are commonly used for lycorine extraction. However, lycorine obtained from these techniques is not pure enough and often mixed with other alkaloids. The great differences in the efficacies of different alkaloids prevent such blending from being directly used. Furthermore, the separation and purification process so required has an adverse effect on and limits the development and utilization of the medicinal value of lycorine.

Lycorine is an analgesic, more so than aspirin, and a hypotensive, as are caranine and galanthine . The analgesic activity exhibited by the Amaryllidaceae alkaloids is attributed to their resemblance to the morphine and codeine skeletons. Lycorine also has antiarrhythmic action, and lycorine hydrochloride is a strong broncholytic. In fact, lycorine shows a relaxant effect on an isolated epinephrine-precontracted pulmonary artery and increases contractility and the rate of an isolated perfused heart. These effects are mediated by stimulation of b-adrenergic receptors.
Lycorine also has a strong inhibitory effect on parasite (Encephalitozoon intestinalis) development and antifungal activity against Candida albicans. Additionally, lycorine has antifeedant, antimalarial, emetic, anti-inflammatory, antiplatelet , as well as antifertility activities. Galanthine, in turn, shows mild in vitro activity against Tripanosoma brucei rhodesiense and Plasmodium falciparum.

ChEBI: An indolizidine alkaloid that is 3,12-didehydrogalanthan substituted by hydroxy groups at positions and 2 and a methylenedioxy group across positions 9 and 10. Isolated from Crinum asiaticum, it has been shown to exhibit antimalarial activit .

Injection: 25mg/ml, for resistance to amebic protozoa and treatment of intraintestinal/extraintestinal amebiasis. Subcutaneous injection: 25–50 mg/injection and 50mg/day.

Great progress has been made in exploration of the pharmacological activities and mechanisms of lycorine and its derivatives in recent years.
1. Effect on Central Nervous System Lycorine can accelerate the mice’s conditioned reflex of motor and defense nature. A mouse intraperitoneally injected with lycorine at 2mg/kg and a rabbit intramuscularly injected with lycorine at 12 or 20mg/kg are exposed to a good sedative effect. For a mouse and a rat injected with lycorine at 12mg/kg and 15 mg/kg, respectively, the sleep time of hexobarbital sodium, pentobarbital sodium, and miltown is extended. According to the hot plate test, the analgesic actions of morphine and rhizoma corydalis are better in a mouse intraperitoneally injected with lycorine at 12mg/kg.
2. Effect on Cardiovascular System Intravenous injection of lycorine results in a slight antihypertensive effect in anesthetized dog, cat, and rabbit, while no inhibitory effect is observed in isolated heart of toad.
3. Anti-inflammatory Effect The lycorine may stimulate the pituitary gland-adrenocortical function, which is possibly relevant to its anti-inflammatory action. Intravenous or subcutaneous injection of lycorine at 3 mg/kg significantly inhibits formaldehyde-induced (rabbit) and albumen-induced (rat) foot swelling. Its inhibitory effect on albumeninduced foot swelling in rat was abolished when adrenal gland was removed.
4. Effect on Smooth Muscle Lycorine can excite the isolated uteri of guinea pig and rabbit, which is free from the counteraction by diphenhydramine. The isolated uterus of rat is excited by a small dose of lycorin but inhibited by a large dose. This effect is relevant to the inhibition by lycorine on cholinesterase.
5. Emetic Effect Lycorine has a good emetic action. The incubation period for emesis is similar to that of ipecine and longer than that of apomorphine, with low toxicity reported. Therefore, it is sometimes used as the emetic for food poisoning.
6. Antitumor Effect According to the invivo experiment, lycorine can inhibit the anaerobic glycolysis of the ascites tumor cells of mice but has no effect on their respiration and aerobic glycolysis. The invitro test indicates that, however, lycorine can lead to a significant inhibition on the aerobic glycolysis of tumor cells but little effect on their respiration and anaerobic glycolysis. Lycorine is capable of inhibiting adenosine triphosphatase, which is possibly relevant to its cytotoxicity.
7. Antiparasitic and anti-malaria effect Dihydrolycorine is better than ipecine in terms of the counteraction against amebic dysentery, with lower toxicity. Thus, it has the potentiality to be a better drug against amebic dysentery. Not only that, dihydrolycorine can be used against paragonimiasis as well.
8. Other Effects Upon the subcutaneous injection of a small amount of lycorine, the blood glucose is observed to be reduced slightly in the target rabbit or rat, with the epinephrine-induced hyperglycemia in the rat relieved. A large amount, however, can only result in a significant rise of blood. Lycorine, similar to SKF-525A, can inhibit drug metabolism to a weak extent. The amebic protozoa can be killed by lycorine. A rat intraperitoneally injected with lycorine at 6mg/kg has more uric acid excreted.

Dihydrolycorine, generated through the hydrogenation of lycorine, has been used clinically due to its better resistance against amebic dysentery and lower toxicity. The amine salt made of lycorine has an antitumor effect in animals.
Lycorine exposure may cause skin irritation (red and swollen) and itching. Nosebleed may be induced in case of inhalation. In case of overdose, it may cause salivation, emesis, diarrhea, bradycardia, cold hands/feet, or even death due to respiratory center paralysis. The major studies of clinical application are focused on (1) antitumor effect, (2) effect on the central nervous system, (3) effect on the cardiovascular system, (4) anti-inflammatory effect, (5) effect on smooth muscle, and (6) emetic effect.

It crystallises as orange crystals from MeOH (m 281-283o), CHCl3/EtOH (m 272-274o), pyridine or from EtOH (m 277o, dec). It has been distilled under high vacuum. The hydrochloride has m 288o (from MeOH/HCl), and the picrate has m 196-197o(from EtOH), [Cook et al. J Chem Soc 4176 1954, Martin & Tu J Org Chem 46 3763 1981, Beilstein 27 II 547, 27 III/IV 6463.]