Dihydro-/3-erythroidine

Dihydro- 3-erythroidine (erythrina isoquinoline) Erythrina spp. (Fabaceae) [seed] nACh-R, a4 32 nACh-R antagonist [nM] [NM blockade effective orally (unlike curare)]... 

The alkaloids and certain of their derivatives from some 28 species of Erythrina have been examined pharmacologically. The most effective of the group, /3-erythroidine and dihydro-/3-erythroidine, have been examined the most extensively. The results of the investigations are summarized in Table 3. 

From all the pure alkaloids tested a- and yS-erythroidine exhibit the highest activity (727). They have been assumed to be the principles responsible for the hypnotic activity of the extracts of the flowers of E. americana 19). /)-Eyrthroidine (225) and its more potent 2,7-dihydro-derivative 226 have been used as muscle relaxant in numerous clinical applications 114, 120). This activity is attributed to an antagonistic action of dihydro-/3-erythroidine to nicotinic acetylcholine receptors, which is now well known and is frequently used in the experimental pharmacology (79, 725, 726). 

Erythroidine behaves as a lactone and when one of its salts with an alkali or alkaline earth metal is catalytically hydrogenated under pressure, a mixture of dihydro-j3-erythroidines, with two tetrahydro- compounds is produced, from which dihydro- -erythroidine can be isolated as the hydrobromide. The dihydro- base has m.p. 85-6° (dec.), + 102-5° and... 

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

Dihydrocinchonicine, 452 Dihydrocinchonidine, 429 Dihydrocinchonine, 428 Dihydrocinchotoxine, 452 Dihydrocodeine, 260 Dihydrocodeinone, 245, 260, 270 Dihydroeodeinone oxime, reactions, 244 Dihydromeiacodeinone, 249 Dihydrocryptopine and isodihydrocryptopine, 296 Dihydrocupreicine, 452 Dihydrocupreidine, 431 Dihydrocupreine, 431 Dihydrodeoxymorphines, 254, 260-2 Dihydroecgonidine, 99 Dihydro- -erythroidines, 387... 

Motoneuron-Renshaw cell synapse Nicotinic nicotine Dihydro- -erythroidine, a-bungarotoxin Excitatory 1 cation conductance... 

The remarkable curariform activity of the Erythrina alkaloids has been discussed in earlier volumes of this series and a review has been published (41). More recent comparison of the activity of dihydro- -erythroidine with standard curare agents such as [Pg.513]

Erysodine (6) has been found to be a competitive, reversible antagonist of nicotine-induced dopamine release. It is equipotent with dihydro-/ -erythroidine (226) and may be a useful tool to characterize neuronal nicotinic acetylcholine receptors (727). 

In view of the fact that the conversion of tertiary into quaternary base other hand, hydrogenation in this series ma have 110 effect on activity (cf. erythraline and its dihydro-derivative ery thramine) or may enhance it (cf. -erythroidine and its dihydride) or mai diminish it (cf. erythramine and its dihydride). 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

Drugs that block the nicotinic receptors on autonomic ganglia, such as hexamethonium, probably do so by actually blocking the Na+ ion channel rather than the receptor. Generally these receptors appear to resemble the central ones more than those at the neuromuscular junction and dihydro-jS-erythroidine is one drug that it is an effective antagonist in both ganglia and the CNS. 

Stolerman IP, Chandler CJ, Garcha HS, Newton JM (1997) Selective antagonism of behavioural effects of nicotine by dihydro-/i-erythroidine in rats. Psychopharmacology 129 390-397... 

Wiley JL, LaVecchia KL, Martin BR, Damaj MI (2002) Nicotine-like discriminative stimulus effects of bupropion in rats. Exp Clin Psychopharmacol 10 129-135 Williams M, Robinson JL (1984) Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue. J Neurosci 4 2906-2911 Witkin JM, Dykstra LA, Carter RB (1982) Acute tolerance to the discriminative stimulus properties of morphine. Pharmacol Biochem Behav 17 223-228 Wooters TE, Bardo MT (2007) The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats. Behav Pharmacol 18 601-608 Wright JM Jr, Vann RE, Gamage TE, Damaj MI, WUey JL (2006) Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats. Pharmacol Biochem Behav 85 507-513... 

Malin DH, Lake JR, Upchurch TP, Shenoi M, Rajan N, Schweinle WE (1998a) Nicotine abstinence syndrome precipitated by the competitive nicotinic antagnist dihydro-beta-erythroidine. Pharmacol Biochem Behav 60 609-613... 

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. 

The pharmacological properties of P-erythroidine and its dihydro derivative are very similar to those of d-tubocurarine and therefore need not be described in any detail. The two compounds differ from curare in three important respects, namely, less potent paralytic action on neuromuscular junctions, briefer duration of paralysis, and oral efficacy. Indeed, gastrointestinal absorption of the alkaloids is so rapid and complete that the difference between effective oral and subcutaneous doses is rather small. Dihydro-P-erythroidine is longer acting than P-erythroidine and about six times as active. Similar to curare, P-erythroidine and its dihydro derivative are antagonized at the neuromyal junction by anticholinesterases such as neostigmine. 

An X-ray crystallographic study of dihydro-j8-erythroidine hydrobromide carried out by Hanson 18) not only confirmed the structures... 

Other pharmacological studies of dihydro-j8-erythroidine in recent years include its effect on cholinergic transmission in the brain 44, 45) and spinal cord 46) and on Renshaw nerve cells 47-49). 

III. C>f these, type II is the most common (10% of neurons in primary culture) and may correspond to a4j32. It is very sensitive to dihydro-jS-erythroidine (10 nM) and is decreased by high concentrations of methyllycaconitine (100 nM). It is also blocked by mecamylamine (I fxM). The most rare and slow responses were termed type III (2%of hippocampal neurons in culture) these may correspond to o 3j34 receptors, are sensitive to I fiM-mecamylamine or 20 ixM tubocurarine, and resistant to 100 nM methyllycaconitine. This classification is likely to hold outside the hippocampus as well, as shown by results in normal and 32-knockout mice [see, for instance, Zoli et al. (212), who distinguish a fourth type of nicotinic response, similar to type III, but with faster desensitization at high nicotine doses and different properties in equilibrium binding assays with agonists]. 

In acute slices, a mixed response, which consists of fast a7-like and slow components, has been described in interneurons of the stratum oriens (36%of all interneurons). The slow response is sensitive to mecamylamine (I/aM) and to a certain extent to dihydro-/3-erythroi-dine (100 nM), but resistant to the o 3j32 antagonist a-conotoxinMII (200nM). In its moderate sensitivity to dihydro-jS-erythroidine, this response may resemble more o 3j34-like responses (type III) than o 4j82 type II responses (218), although it has been suggested... 

When it comes to heteromeric receptors, many antagonists have little useful selectivity. The exceptions are dihydro-j8-erythroidine and the rapidly growing family of the a-cono-toxins (see below). An important point is that many of the antagonists available have channel-blocking properties (see, for instance, mecamylamine and hexamethonium). 

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