Abstract
Ach (180) is the cationic neurotransmitter that in the central and peripheral nervous systems effects the transmission of action potentials across nerve-nerve and neuromuscular synapses. In response to an action potential it is released from the presynaptic nerve and then diffuses across the synapse ultimately to bind to the Ach receptor which serves, amongst other functions, as an ion gate for the entry of K⊕ into either the postsynaptic nerve process or the muscle or gland cell, the series of events that then follows ultimately resulting in the triggering of an action potential in the postsynaptic cell (Brand 1960; Gearien 1970; Greig et al. 1995a; Quinn 1987; Rosenberry 1975).
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Notes
- 1.
Organophosphate Cholinesterase Inhibitors (including “nerve gases”)
The cholinesterase inhibitors of the organophosphate group, which have already been the subject of extensive review (Gaddum 1954; Holmstedt 1959; Marrs 1993; Silver 1974a; Soreq and Zakut 1993; Taylor 1996), can be denoted by the general formula 270 in which “R1 and R2 are capable of almost infinite variation. They may represent alcohols, phenols, mercaptans, amides, or alkyl or aryl groups attached directly to the phosphorus, etc. Common Y radicals are from fluorine, 4-nitrophenol and phosphates (in a “pyrophosphate”), but in other inhibitors Y may be cyanide, thiocyanate, an enol, a carboxylate, chloride or almost any phenoxy or thiophenoxy” (Holmstedt 1959) and “Y may contain a quaternary nitrogen atom and X may be either O or S” (Holmstedt 1959). Examples of this group of inhibitors containing these above structural functions in a variety of combinations have been presented in extensive (Holmstedt 1959) and less extensive (Silver 1974a; Taylor 1996) tabulations.
It has been stated that “The effects of organic phosphates on cholinesterase were discovered in various different ways. Tetraethylpyrophosphate (TEPP) which is one of the most active of these substances was first described as long ago as 1854 by de Clermont who said, among other things, that it had a burning taste. It has been unkindly said that the fact that de Clermont survived to tell the tale [a few drops should have been lethal (Taylor 1996)] makes it doubtful whether he really did succeed in making TEPP at all” (Gaddum 1954). The first published account of this group of substances (in the form of the esters of monofluorophosphoric acid) appeared in a paper by Lange and Krueger (1932) who accidently discovered that their odour was pleasant and aromatic but, a few minutes after inhalation, headache and breathlessness occurred followed by photophobia. The latter observations were apparently instrumental in the years beginning in the middle thirties, namely a few years before the outbreak of World War II, in leading a team led by Schrader at Farbenfabriken Bayer in Germany to investigate this class of compound for insecticidal activity. One of the early compounds from approximately 2,000 that were synthesised was Parathion (270, R1=R2=EtO, X=S, Y=4-NO2C6H4O) (Witkop 1998) that was to find use as an agricultural insecticide, in which role it also led to numerous cases of accidental poisoning. Another two compounds – which because of their extremely high toxicity in man were regarded as potential warfare agents and were therefore kept secret for several years – that were produced by Schrader’s group were Sarin (271) (Witkop 1998) [the structural analogue Soman (272) was also to prove to be an extremely toxic “nerve gas”] and Tabun (273) (Witkop 1998). Discoveries similar to those in Germany were made at the University of Cambridge by an extra-mural Ministry of Supply research team working under the direction of McCombie and Saunders during World War II and likewise – after a suggestion was put forward at the time of the Munich crisis in 1938, when war seemed imminent, for a study of the action of war gases on enzymes was not proceeded with – by a research team under the direction of Dixon working for the Chemical Defence Research Department of the Ministry of Supply in the Department of Biochemistry at Cambridge. For obvious security reasons, the results of these investigations were withheld from publication although secret reports – which were also made available to American workers almost from their inception – were from time to time submitted to the Ministry of Supply. However, from 1946 and onwards, following the cessation of hostilities, comprehensive summaries of this wartime research at Cambridge {which from the statement that “Until this work began in Cambridge in 1941, the alkyl fluorophosphates had received practically no attention. Lange [(Lange and Krueger 1932)] gave a tedious and laborious method for preparing dimethyl and diethyl fluorophosphates in very poor yields as follows.....”(McCombie and Saunders 1946) may appear to have received its genesis in the earlier German studies (vide supra)} have appeared (Dixon and Needham 1946; McCombie and Saunders 1946; Saunders 1947 – see also Henry 1949). Primarily it involved the synthesis and biological evaluation of alkyl fluorophosphates, the miotic action of which was noticed because of their effect on the eyes of those working with them, and ultimately lead to the discovery of the toxic effects of diisopropyl fluorophosphate (DFP) (270, R1=R2=Me2CHO, X=O, Y=F).
Thus, through the combined efforts in both Germany and the UK of the World War II machines were synthesised and biologically evaluated some of the most lethal of known synthetic compounds, namely Sarin (271), Soman (272), Tabun (273) and DFP (270, R1=R2=Me2CHO, X=O, Y=F), which thus became available for use as insidious chemical warfare “nerve gases”. What an appalling legacy for the world’s inhabitants!
‘Peace on earth!’ was said. We sing it,
And pay a million priests to bring it.
After two thousand years of Mass
We’ve got as far as poison gas.
[Thomas Hardy, Christmas: 1924 as quoted by Macinnis (2004) POISON AND WAR, Chapter 9. These sentiments were expressed when “gas-warfare” was limited to the use of the likes of chlorine, phosgene and mustard gas. However, they are currently certainly apposite in view of the incident during the protracted civil war in Syria where, during August 2013, a nerve gas was shamefully used against the civilian population of which a total of some thousands were either murdered or severely injured.]
Such is the nature of the human creature. However, through the more worthy and less destructive efforts of this same species, either l-physostigmine (Sect. 10.7.1) or its enantiomer (Sect. 10.9) have both been found to provide prophylactic protection against intoxication by organophosphates (including “nerve gases”) which is now known to occur via a progressive and virtually irreversible inactivation of AchE and other esterases by alkylphosphorylisation, involving in the former enzyme the hydroxyl group of the serinyl 198 moiety (Sect. 10.1.1 and Fig. 10.3) to afford 274 (Adrian et al. 1946; Porter et al. 1958; Rydon 1958; Silver 1974a; Taylor 1996; Witkop 1998). The slow rate of hydrolysis of the N-methylcarbamylated AchE (Fig. 10.1) is far surpassed by the almost irreversible combination of the so-called “nerve gases” as shown in 274 (Witkop 1998).
However, and fortunately in view of their widespread use, particularly in agriculture and horticulture and as insecticides, antidotes to the associated poisoning by organophosphates have been developed. These have been comprehensively reviewed (Holmstedt 1959; Silver 1974a; Taylor 1996) and consist of nucleophilic compounds, the most efficient being some of those with a strongly ionisable oxime (=NOH) group, which have a high affinity for phosphorus and thereby effect reactivation of the AchE by eliciting dephosphorylisation with liberation of the serinyl 198 hydroxyl group from the 274 moiety. Although not all oximes and hydroxamic acids are equally effective in this respect, they can also afford protection from poisoning if administered prior to exposure to the organophosphate (Holmstedt 1959) but in cases where this has already occurred, speedy treatment is essential since the phosphorylated enzyme “ages” to form the corresponding acid which is unable to react with the anionic oxime (Silver 1974a).
- 2.
It has been noted in review (Luo et al. 2006), that “human cholinesterases ....... contain up to 583 amino acids, have a molecular mass of 70-80 kDa and are variably glycosylated. Three-dimensional analyses of AChE and BChE, based on X-ray crystallography, have provided structural information regarding the positioning of the catalytically important amino acid residues within these proteins. In synopsis, three major binding domains have been described within AChE and two within BChE in an internalized, primarily hydrophobic gorge of some 20Å length but as narrow as 0.5Å wide. Deepest within this gorge is a catalytic acyl binding domain, which hydrolyses choline esters through electron transfer within a catalytic triad, termed a charge relay system. The triad includes Ser200, the imidazole of His440, and the carboxylic acid moiety of Glu327 (TcAchE numbering)..........”
- 3.
Whilst accepting that much of the early work on P.venenosum and the Calabar bean and its major alkaloidal component, l-physostigmine, was carried out in the University of Edinburgh (see footnote 8 of Chap. 1), this nevertheless contentious statement ignores the work of many others, such as, for examples, the Polonovski brothers – Max and Michel, and Robert Robinson and his co-workers, which contributed significantly to the structural elucidation of the alkaloid (Sect. 2.2) and the later pioneering studies of Julian and Pikl in the USA, of Kobayashi in Japan and of Robert Robinson in the UK, and their co-workers, which led to its first synthesis by Julian and Pikl (Sect. 2.3.1).
- 4.
In connection with these investigations, it has been stated that “The work of STEDMAN and co-workers stands as one of the high points in the structure-activity area and places them among the pioneers of this method of experimental approach which has yielded many active therapeutic agents in most branches of medicine” (Long 1963) and that they “were pioneers in chemical pharmacology” (Long and Evans 1967).
- 5.
For almost a century following its first isolation, l-physostigmine, and later together with l-physovenine (one of its alkaloidal companions in the Calabar bean) (Chap. 3), were the only alkaloids whose biological activities were associated with the inhibition of AchE (see footnote 8). Indeed, published opinion as to the occurrence of antiAchE activity within the alkaloid kingdom would appear to be divided. Thus, although the statement that “Alkaloids with strong cholinesterase inhibiting properties are a rare occurrence in the Plant Kingdom” (Holmstedt 1972) has been corroborated by “Alkaloids with strong anticholinesterase activity are very rare among plants” (Neuwinger 1996), it had earlier (Goldstein 1951) been pointed out that “The reversible inhibitors [of AchE] comprise a structurally diverse group whose only common feature is the presence of basic nitrogen [see also Sect. 10.1.1]. Indeed, it would appear that every alkaloid ever tested is an inhibitor at some concentration”. This assertation, which was accompanied by the observation that such activity is found with amphetamine, atropine, methylene blue, procaine, quinine hydrochloride and morphine [see also (Eadie 1941, Wright 1941)] and strychnine sulphates, has found support from the following reports:-
-
5.1.
Investigations by Beaujard (1944) and Vincent and Beaujard (1943, 1945) have led to the recognition of diverse alkaloidal antiAchEs. Perhaps not surprisingly, l-physostigmine was found to be by far the most active, geneserine was less active (see footnote 9) and in further decreasing order of activity were reported (Vincent and Beaujard 1943, 1945) pelletierine, ibogaine, conine (conicine), colchicine, strychnine, ergotinine, quinidine, papaverine, spartéine, quinine, emetine, cocaine, ergobasine, cinchonidine and cinchonine [only reported by (Vincent and Beaujard 1943)], thébaine, hyoscyamine, ergotamine [see also (Boyd et al. 1960)], versatrine, narcotine, narcéine, brucine, hordenine, dicodid [only reported by (Vincent and Beaujard 1943)], ephédrine, atropine, morphine (see also Eadie 1941; Vincent and Maugein 1942b; Wright 1941) dionine, yohimbine see also (Boyd et al. 1960) and apomorphine see also (Henry 1949), to be followed (Vincent and Beaujard 1943) by − in further decreasing order of activity − aconitine, mescaline, eucodal, codeine and heroine (Vincent and Maugein 1942b), cytisine, nicotine, pilocarpine, scopolamine and arécoline, – with the last four compounds being inactive, and (Vincent and Maugein 1942b) dihydroxicodienone.
-
5.2.
Later investigations (Raymond-Hamet et al. 1956) showed that akuammine (see also Creasey 1983(b)), harmaline, harmalol, harmine, ibogaine and quebrachamine (see also Creasey 1983(e)) “strongly inhibit the cholinesterase of horse serum and have a much weaker inhibiting action on the cholinesterase of sheep brain” – “in any case their action is weaker than that of physostigmine” and that (Levy-Appert-Collin 1969, 1978) pseudo-akuammigine is a more potent antiBchE than it is antiAchE. Yohimbine in high concentrations exhibits antiAchE activity (Creasey 1983(d); Boyd et al. 1960; Tanaka et al. 1978) as does ergotamine (Boyd et al. 1960).
-
5.3.
In 1952, galanthamine (275) was isolated from the Caucasian snowdrop, Galanthus woronowii Lozinsk (family Amaryllidaceae) (Holmstedt 1972; Wildman 1960), a plant native to Georgia in the USSR (Holmstedt 1972), and in the following year the same alkaloid, but now named lycoremine, was found in Lycoris radiata (Wildman 1960) and it has since been obtained “from the bulbs of a number of Amaryllidaceae plants” (Irwin and Smith 1960b) and “often is a constituent of the Galanthus, Leucojum, Narcissus and Vallota species” (Wildman 1960). Two other potential sources for it have also been suggested, both of which are snowdrops, namely Leucojum aestivum L. and Ungernia victoris Vved, which are often found on the Caucasian part of the Black Sea coast and grow in the southern parts of Central Asia, respectively (Holmstedt 1972). Catalytic hydrogenation of galanthamine afforded dihydrogalanthamine (276, R1=Me, R2=OH, X=NMe) which was found to be identical with lycoramine, an alkaloid that in 1932 had been isolated from Lycoris radiata (Wildman 1960), a subsequent botanical source of galanthamine (vide supra).
A century was to elapse from the discovery of that of l-physostigmine before another group of alkaloids with strong antiAchE activity was found (Holmstedt 1972) when galanthamine (275) was found to have potent antiAchE activity (Brossi et al. 1996; Holmstedt 1972), namely it is more active than pyridostigmine (189 R1=R2=Me) but less active than neostigmine bromide (188, R1=R2=Me, X=Br), and lycoramine (276, R1=Me, R2=OH, X=NMe) and is about equiactive with pyridostigmine (189 R1=R2=Me) (Irwin and Smith 1960a). As might have been expected, the methiodides of galanthamine and of deoxydemethyl lycoramine exhibit potent antiAchE activity (Irwin and Smith 1960b). Further structural modification, involving the introduction of a carbamyl function and quaternisation, afforded (276, R1=Me2NCO, R2=H, X=⊕NMe2IƟ) which is even more potent (Holmstedt 1972; Irwin and Hein 1962; Irwin et al. 1961). Galanthamine (275) has been used in the treatment of Mysasthenia gravis (Sect. 10.6.1) (Irwin and Smith 1960a) and other neurological diseases (Holmstedt 1972) and has been investigated for development for the treatment of Alzheimer’s disease (Sect. 10.7.2) (Brossi et al. 1996; Greig et al. 2005a; Klein 2007; Muñez-Ruiz et al. 2005; Thomsen et al. 1991).
-
5.4.
Huperzine (277), indigenous to China and isolated from the clubmoss Huperzia serrata, possesses antiAchE activity and is useful in the treatment of Myasthenia gravis (Chapter 10.6.1) and has been investigated for development for the treatment of Alzheimer’s disease (Sect. 10.7.2) (Brossi et al. 1996; Hanin et al. 1991).
-
5.1.
- 6.
Dedication
To the loving memory of my brother Roger and his wife Barbara. Together they introduced me to God’s own country of the North Yorkshire Moors National Park and many of its wonders. These, including especially the delightful village of Lastingham and its beautiful Ancient Crypt Church of St Mary (vide infra), we together shared with much joy and happiness on so many occasions.
Sydney Ringer (1835-1910) (Elliott 1914; Miller 2007)
The name of Sydney Ringer is perpetuated today in Ringer’s solution, the physiological saline which he invented during his work as a physiologist, pharmacologist and Professor of Medicine at University College, London. It is best known as the “drip” in evidence in hospital wards and operating rooms, and at accident sites but has also played a fundamental role – and continues to do so via pharmacological and physiological research using either modern cell culture media or either blood or tissue fluid replacement salines – in the advancement of medical science.
As well as his being primarily a physician in the University College Hospital, where one aspect of his research, as it had been that of others in 1869, 1871 and 1872 (Holmstedt 1972), involved the use of “Physostigma” in the treatment of nervous affections (Ringer and Murrell 1877), the “lectureship” in pharmacology in the college was “rendered illustrious by the name of Sydney Ringer” (Gaddum 1962). Upon his retirement, this ultimately led to the appointment of Arthur Cushny (1866-1926) [who played an important role in establishing pharmacology as a science and, as one of his main interests, was to effect important pioneering studies into biological relationships between optical isomers (Cushny 1926) (Sect. 10.9)] as the first Professor of Pharmacology in 1905 (Gaddum 1962). After thirteen years, Cushny moved to the inaugural chair in pharmacology in the School of Medicine at the University of Edinburgh (see footnote 8 of Chap. 1) where much of the early work upon Physostigma venenosum and l-physostigmine, the apparently (see Sect. 8.2) major alkaloidal component of its seeds (Calabar beans), was effected (Gaddum 1962) (see footnote 8, 9 and 10 of Chap. 1, Sects. 2.1, 2.2, and 10.1.1, 10.5). Included in this were the pioneering investigations into the physiological actions and therapeutic uses of the Calabar bean by TR Fraser (NOTE 20) whose appointment to the Chair of Materia Medica at Edinburgh had been “supported by a large number of famous people, including Sydney Ringer……” (Gaddum 1962) (see footnote 8 of Chap. 1).
However, as well as his contribution to medical practice and research, Sydney Ringer’s name is also synonymous with the Ancient Crypt Church of St Mary in the village of Lastingham (vide supra). This association transpired as a result of his purchase in Lastingham of a house, St Mary’s, which still stands, albeit now somewhat extended, in Anserdale Lane. Although this property eventually became his retirement home, throughout his late professional and earlier married life his principal home was 15 Cavendish Place, just off Regent Street and close to Harley and Wimpole Streets, Marylebone, W1 in London, and it was only for holidays and weekends that he visited his second home in Lastingham. Nevertheless, he became a leading member of the Parish, becoming a church-warden and a manager of the school – and in August 1867 he married Miss Ann Darley, the eldest child of Henry Brewster Darley, a Lord of the Manor of Lastingham.
The Ringers had two children, the eldest being Annie and the youngest being Hilda (née Sydney Ringer). Despite being availed of the then finest medical attention, Annie tragically died at the family home in London (vide supra) when she was only seven years old after a brief illness resulting from an intestinal obstruction. Her body was interred in the churchyard at Lastingham and her grave is now adjacent to that where her parents were later to find their final resting place. In memory of their daughter Annie, Sydney and Ann Ringer in 1879 became the benefactors of a substantial and major restoration of St Mary’s Church which was then in a very sorry state of disrepair, having been built beginning in 1078 upon the site of the Celtic monastery founded circa 654 by St Cedd from Lindisfarne who, following his death at Lastingham from plague, was succeeded as abbot by his brother St Chad. The result of this restoration is currently to be found in the wonderful Church of St Mary with its unique seventh century Saxon crypt – the location of the shrine of St Cedd – buried to the right of the altar, which has remained virtually unchanged since the time of William the Conqueror with the beautiful serenity of its celestial atmosphere. Perhaps not surprisingly, most of the stained glass windows in this church are Ringer memorials although, curiously, in several of these, Ringer’s Christian name is misspelled as Sidney (rather than the name associated with one of Australia’s major cities) [as it also is in (Elliott 1914) (vide infra)] and those of his wife and elder daughter as Anne.
Sydney Ringer died in 1910, having been predeceased by his wife Ann in 1897. They were survived by their second daughter, then Mrs Hilda Kayler, and it was she who, in 1912, endowed the Sydney Ringer Memorial Lecture to be delivered biennially at University College Hospital. As part of the inaugural presentation of this lecture in June 1914, it has been stated (Feldberg 1979) that TR Elliott (1914), by then an assistant physician to the hospital, “brilliantly anticipated and conceived the idea of chemical transmission in the autonomic nervous system”, although it has been noted (Bacq 1975) that it was a decade earlier that Elliott then had expressed “himself clearly on chemical transmission … .. In a short prophetic note presented to the Physiological Society on May 21, 1904” when he wrote “Adrenaline [the actual neurotransmitter was ultimately found to be Ach (180) (Sects. 10.1.1 and 10.3)] might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery” (Elliott 1904) (Sect. 10.3).
- 7.
“With this two-fold experimental evidence the cholinergic nature of ganglionic and neuromuscular transmission was actually established although it took years before it was generally accepted. For the conversion of the strongest opponent, Eccles, we had to wait for over ten years” (Feldberg 1979). Thus, for example, it was stated in review (Henry 1949) that “It should be added that this essentially classical hypothesis does not tell the whole story of this physiological problem, and an interesting account of an electrical experiment of transmission has been given recently by Eccles [1945], and Cunliffe, Barnes and Beutner have called attention to the electrogenic properties of acetylcholine”. Who were these opponents?
They were the electrophysiologists who were in 1942 of the opinion that “It has now been established that neuromuscular transmission is mediated by the local negative potential which a nerve impulse sets up at the end plate region of a muscle fibre....Similarly, it has been shown that synaptic transmission may be mediated by the local negative potential” (Bacq 1975), a concept that had been further elaborated (Eccles 1945). Details of the evolution of this controversy over the years and of its ultimate solution have already been well and thoroughly presented (Bacq 1975; Eccles 1945; Feldberg 1979 – see also Sourkes 1966(ab)). In 1963, JC Eccles along with AL Hodgkin and AF Huxley were jointly awarded the Nobel Prize in Medicine and Physiology “For their discoveries concerning the ionic mechanisms involved in the excitation and inhibition in the peripheral and central portions of the nerve cell membrane” [Sourkes 1966(c)].
- 8.
It has been stated that “Although many alkaloids (Henry 1949) other than physostigmine have been isolated from the Calabar bean, apparently they have not been investigated for anticholinesterase (anti-ChE) activity” (Long 1963) and that “Although many alkaloids other than physostigmine have been isolated from the Calabar bean, they have not been evaluated for anticholinesterase or pharmacological activity” (Long and Evans 1967). However, it would appear that both of those related claims are at variance with the majority of the observations reported in the remainder of this NOTE and some of those reported in See footnote 9.
Included in the report (Salway 1911) announcing the first isolation from Calabar beans of l-physovenine (Sect. 3.1) [and the second isolation of l-eseramine ( 4.1)] was the observation that “Physovenine is, like physostigmine, very powerfully myotic [whereas no such activity whatsoever was ascribed to l-eseramine]; thus a single drop of 0.1 per cent solution of the alkaloid in dilute alcohol when introduced into the eye produced after an interval of a few minutes a powerful contraction of the pupil, which attained its maximum effect half an hour after the injection”. Moreover, others have noted that physovenine “a une action myotique beaucoup plus forte que l’ésérine” (Polonovski and Nitzberg 1915a) and has “a strong myotic action” [once again, a myotic action was not ascribed to l-eseramine] (Kerharo and Bouquet 1950) and, in broader context, “appears to be at least as poisonous as physostigmine” (Henry 1924).
These above observations have been further supported by the results from investigations (Ainscow et al. 1964) into the ability of l-eseramine and l-physovenine to potentiate the action of Ach on the frog rectus abdominus muscle (by the inhibition of AchE) and to reverse the effect of a tubocurarine block on the rat diaphragm-phrenic nerve preparation (by potentiation of the action of Ach). With both preparations l-physovenine shows the same order of activity as l-physostigmine, whereas the activity of l-eseramine is much lower (Ainscow et al. 1964). This latter observation was confirmed using Electric Eel AchE when it was also found that l-eseramine had only 0.7% of the potency of l-physostigmine (Yu et al. 1988a – see also Atack et al. 1989) – and, interestingly, also that all other analogues of physostigmine resulting from replacement of the methyl group at either N(2) (Atack et al. 1989, Yu et al. 1988a) or, surprisingly (see Sect. 10.7.2), within the carbamyl moiety (Atack et al. 1989) were only weak antiAchEs.
- 9.
It has been stated (Bacchi et al. 1994) that “geneserine inhibits acetylcholinesterase activity” although the presumably-supportive primary literature referred to (Brufani et al. 1986, 1987; de Sarno et al. 1989; Marta et al. 1988) unfortunately refers neither to such activity for geneserine nor even to the alkaloid whatsoever. However, from the results of several investigations (Bozonnet 1936; Kahane and Lévy 1936, 1937; Orzechowski and Hundreiser 1936; Polonovski et al. 1952; Vincent and Beaujard 1943, 1945; Vincent and Maugein 1942b; Vincent et al. 1961) it has been concluded (Robinson 1964b) that “geneserine shows anticholinesterase activity, but not to the same degree as does physostigmine” Indeed, it has also been concluded (Polonovski and Nitzberg 1915a) that, with regard to myotic action, geneserine is practically inactive and a summary (Henry 1924) of experimental observations (Polonovski and Combemale 1923) states that “Geneserine is not myotic and has generally a much weaker action than physostigmine and is less toxic”.
Pharmacological studies have also been carried out investigating the effect of l-geneserine upon the rabbit thyroid gland (Carrière et al. 1939), the guinea pig thyroid gland (Gineste and Parigot 1959), the endocrine function of the guinea pig pancreas (Gineste and Burin 1958), the inhibition of rat-brain monoamine oxidase (Vincent et al. 1961), gastric secretion in man (Filinski and Rostkowski 1927), neuromuscular excitability (Lobstein 1935) and salivary and pancreatic secretion (Polonovski and Combemale 1923).
- 10.
In 1854-1855, Robert Christison (see footnote 8 of Chap. 1) published the following cautionary observations with regard to the kernels of Calabar beans:-
“They are white and hard, but may be chewed; and they have the taste of the eatable leguminous seeds, without bitterness, acrimony, aroma, or any other impression on the organs of taste; in fact, they are scarcely, if at all, distinguishable in taste from a haricot-bean. This is a formidable peculiarity, were it possible for the seed to become a familiar poison in Europe.” (Christison 1854 – 1855, 1855).
It is, therefore, perhaps not surprising that cases of poisoning, either accidental or malicious, with the Calabar bean have been reported (Sect. 10.13).
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Robinson, B. (2023). Biological Activities of the Alkaloids of the Calabar Bean. In: The Calabar Bean and its Alkaloids. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1191-1_10
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