Curare-like activity

The nitrogen atom in quinolizidine derivatives behaves as a tertiary amine and hence it can undergo quaternization by reaction with alkyl halides. For instance, berberine derivative 101 was transformed into 102 by treatment with 3-iodopropanol followed by anion exchange. Compound 102 was then transformed into intermediate 103, which was employed as a precursor for the the preparation of bis-ammonium salt 104 (Scheme 10). This compound showed ultrashort curare-like activity in rhesus monkeys <2001JOC3495>. 

Dzhakhangirov, F. N. and Bessonova, I. A. 2002. Alkaloids of Aconitum coreanum. X. Curare-like activity - Structure relationship. Chemistry of Natural Compounds, 38(1) 74-77. 

Decamethonium, a synthetic drug with potent curare-like activity... 

Si,Si-Dimethyl-Sila-Substituted Derivatives of Polymethylen-bis-Trimethyl-ammonium Compounds with Curare-Like Activity... 

A C6Si2 O-skeleton with a C3SiOSiC3 sequence should also lead to a similar N—N distance. Only a little shortening is expected because of the Si—O bond length and SiOSi bond angle. According to this concept, the disiloxanes 213—215 should also exhibit curare-like activity. 

In the mice head-drop test for curare-like activity compounds 210, 212 and 213 were found to be very potent. In analogy to d-tubocurarine, decamethonium and other muscle relaxants, these compounds cause a neuromuscular block when administered intraperitoneally. 

Erythrina alkaloids, possessing curare-like activity, are a large class of natural products found in Erythrina plants (Leguminosae). In a study towards construction of the erythrina skeleton, disfavored 5-endo-trig cyclizations were achieved by Ikeda et al. by BusSnH-mediated radical cyclization of an //-vinylic a-chloroacetamide to give five-membered lactams... 

The beanlike seeds of the trees and shrubs of the genus Erythrina, a member of the legume family, contain substances that possess curare-like activity. The plants are widely distributed in the tropical and subtropical areas of the American continent, Asia, Africa, and Australia, but apparently they are not used by the natives in the preparation of arrow poisons. Of 105 known species, the seeds from more than 50 have been tested, and all were found to contain alkaloids with curariform properties. Erythroidine, from E. americana, was the first crystalline alkaloid of the group to be isolated. It consists of at least two isomeric alkaloids, a and P-erythroidine both are dextrorotatory. Most experimental and clinical study has centered on the b form because it is more readily obtainable in pure state. P-Erythroidine is a tertiary nitrogenous base. Several hydrogenated derivatives of p-erythroidine have been prepared of these, dihydro-P-erythroidine has been studied most carefully and subjected to clinical trial. Conversion of P-erythroidine into the quaternary metho salt (p-erythroidine methiodide) does not enhance, but rather almost entirely, abolishes its curariform activity this constitutes a notable exception to the rule that conversion of many alkaloids into quaternary metho salts results in the appearance of curare-like action. 

Curare-like activity, lowered blood pressure (dogs) antagonized phenylephrine-induced contractions of isolated rabbit aorta blocked neuromuscular transmission in rat hemidiaphragm preparation 440... 

A variety of silylated alkylamines showing a wide diversity of biological activity have been studied. For example, a series of silylated amines is reported to have long-term insect-repellent activity (up to 30 days) compound 10 is typical of the group (53). Silylalkylamines having quaternary ammonium groups, such as 11, have been reported to have curare-like activity (54). 

Cynoglossum officinale (hound s tongue) contains alkaloids with curare-like activity as well as hepatotoxic and carcinogenic pyrrolizidine alkaloids, which are covered in a separate monograph. 

Russian workers have prepared for pharmacological studies simple carbamates of trachelanthamidine (68) by treatment with the appropriate isocyanate. Some cholinesterase inhibitors based on the standard decamethonium model have been prepared. Decamethylene bistrachelanthamine dibromide (69) showed marked curare-like activity in cats and rabbits. New procedures for the iodometric determination of platyphylline bitartrate and for the colorimetric determination of trichodesmine and incanine in the organs of poisoned animals have been described. 

Typical physiological effects exerted by tropane bases hitherto known are essentially as follows (l) mydriatic, i.e., parasympathetic blocking, (2) anesthetic, (3) stimulating the central nervous system. Recently (4) ganglion blocking, i.e., curare-like activity, has been detected in some synthetic tropeines. 

Bungarotoxins. Toxins of the very poisonous southeast Asian snake Bungarus multicinctus (striped krait, Elapidae). Crude extract of venom LD50 (mouse s.c.) 0.019 to 0.33 mg/kg. The postsynaptic neurotoxin a-B. is a polypeptide (Mr ca. 8000) of 74 amino acids and 5 disulfide bridges exhibiting curare-like activity. jS-B. contains different polypeptides and is a pre-synaptic neurotoxin. 

Dzhakhangirov FN, Bessonova lA. Alkaloids of Aconitum coreanum.X. Curare-like activity—Structure relationship. Chem Nat Comp 2002 38(l) 74-7. 

Important toxins are cobramine A and B from cobra toxin and crotactine and crotamine from crotox-in, the toxin of the North American rattlesnake. The toxic proteins are classified according to their mode of action cardiotoxins, neuFotoxins and protease inhibitors (with inhibitory activity toward chymotrypsin and trypsin). Cardiotoxins (heart muscle poisons) cause an irreversible depolarization of the cell membranes of heart muscle and nerve cells. Neurotoxins (nerve poisons) show curare-like activity they prevent neuromuscular transmission by blocking the receptors for the transmitters at the synapses of autonomic nerve endings and at the motor end plate of skeletal muscle. Protease inhibitors inhibit acetylcholine esterase and similar enzymes involved in nerve transmission. 

Compounds of this structure have been investigated for ganglion-blocking and curare-like activity [200-202]. 

---