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Panax quinquefolium (American Ginseng) and Physostigma venenosum (Calabar Bean)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Sushweta Mahalanobish, Noyel Ghosh, Parames C. Sil
The active ingredients of CB include physostigmine (eserine), eseridine, eseramine, calabarine, and phytosterin which were first isolated in the 19th century (Swain, 1972). Though a number of other derivatives were identified later, physostigmine is still considered the most important alkaloid of CB (Miller, 1976; Zhao et al., 2004). Physostigmine is highly soluble in chloroform, benzol, alcohol, and carbon disulphide and relatively less soluble in water. Physostigmine is highly unstable, and light or heat exposure converts it into red color rubreserin (Hemsworth and West, 1970; Rubnov et al., 1999). The interaction between the functional carbamate group of physostigmine at the cholinesterase active site occurs in a way similar to that of the organophosphorus-mediated inhibition of cholinesterase (Coelho and Birks, 2001; Somani and Dube, 1989). Physostigmine contains two stereocenters – the two carbons where the five-membered rings join together. Among 71 derivatives of physostigmine, 33 are racemic mixtures, and 38 are the product of a single enantiomer. In 1935, Julian and Pikl first synthesized total physostigmine. They prepared (L)-eseroline by hydrolysis of N-methylcarbamoyl group of physostigmine. (L)-eseroline has an effect similar to morphine as it exhibits a high affinity for opioid receptor sites. Calabarine, an ether-insoluble alkaloid is produced as a by-product of physostigmine synthesis and can be converted back to physostigmine by warming with diluted acid (Zhao et al., 2004). Its physiological action has a closer resemblance to strychnine than physostigmine. Other derivatives include epistigmine (heptyl-physostigminetartrate), cymserine, bisnorcymserine (N-demethylated cymserine), and tetrahydrofurobenzofuran cymserine. Phenserine is a phenylcarbamate derivative of physostigmine. Posiphen ((+)-phenserine), is an enantiomer of (-)-phenserine. Rivastigmine is the only physostigmine derivative that is prescribed for moderate to mild dementia treatment. Figure 10.2 depicts bioactive constituents of CB.Bioactive constituents of CB.
A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017
Published in Expert Opinion on Therapeutic Patents, 2018
Vincenza Andrisano, Marina Naldi, Angela De Simone, Manuela Bartolini
Cholinesterase inhibitor (ChEIs) accounted for over 40% of the total market of drugs for AD treatment in 2011. The rationale basis for their clinical use has been paved back in the ‘80s when the so called ‘cholinergic hypothesis’ was formulated [21]. ChEIs temporally compensate the cholinergic deficit typical of AD by increasing ACh levels, enhancing cholinergic transmission in the brain and temporally ameliorating the cognitive symptoms. Notwithstanding the cholinergic dysfunction is not a causative event in the disease onset but, likely, a downstream effect of earlier alterations, ChEIs are still the major class of drugs used in AD treatment. Indeed, out of four medications currently available on the market, three (donepezil, galantamine, and rivastigmine) are ChEIs [22] while the fourth is memantine, a non competitive antagonist to N-methyl-d-aspartate (NMDA) receptors. The approval of anti-ChE drugs for AD treatment by FDA dates back in the ‘90s (1992–2000). Recently (2014) a combination of donepezil and memantine was also approved. Among currently available drugs, donepezil and galantamine are selective AChE inhibitors (AChEIs), while rivastigmine is active also toward BuChE, but none of them is marketed as selective BuChE inhibitor [23]. All these drugs were developed when knowledge on the role of BuChE in AD was only partially disclosed and resulted from an intensive research focused on highly selective and centrally active AChE inhibitors, in the attempt of limiting peripheral adverse effects. Conversely, some reports have shown that highly selective BuChEI such as cymserine [24], (−)-N1-phenethylnorcymserine (PEC) [25], optical isomers of N1-norphenserine [26] and BuChE-selective phenserine derivatives [27] could enhance learning ability and beneficially affect amyloid production/deposition. Furthermore, recent clinical findings have highlighted that BuChE selective inhibitors may be more effective than AChE inhibitors in severe AD [5]. Outcomes from clinical trials have also suggested that the positive effects of rivastigmine are partially mediated by the inhibition of BuChE. Finally, retrospective analyses of clinical trials on rivastigmine provided evidence that BuChE genotype may also influence treatment response [5].