Physostigmine, acetylcholinesterase inhibition

Heptylphysostigmine (251) is a more lipophilic homolog and is reported (318) to be less toxic than physostigmine, while retaining its in vitro acetylcholinesterase inhibiting potency. 

Mach M, Grubbs RD, Price WA, Paton SJ, Lucot JB (2004) Behaviraal changes after acetylcholinesterase inhibition with physostigmine in mice. Pharmacol Biochtan Behavira- 79 533... 

Physostigmine reversibly inhibits the action of the enzyme acetylcholinesterase thereby increasing the level of acetylcholine in the synaptic cleft of the neuromuscular jimction thereby counteracting the agent s pharmacological effects. 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

Physostigmine is one of the major alkaloids in calabar bean. It has been shown to inhibit acetylcholinesterase at low concentration and to reverse the toxic effects resulting from diazepam overdose. The phytostigmine skeleton is easily obtained in very good yields from an appropriate non-stabilized imidate methylide.162,292,465... 

Adverse effects The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia may also occur. Inhibition of acetylcholinesterase at the skeletal neuromuscular junction causes the accumulation of acetylcholine and ultimately results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses. 

Perola E, et al. Long-chain analogs of physostigmine as potential drugs for Alzheimer s disease new insights into the mechanism of action in the inhibition of acetylcholinesterase. Biochim. Biophys. Acta, 1997, 1343(1), 41-50. 

The main action of physostigmine is on the parasympathetic nervous system. It is now known (52, 53) that physostigmine produces its effect by inhibition of the enzyme acetylcholinesterase. The role played by acetylcholinesterase in the transmission of nerve impulses at nerve endings (54, 55) and in the conduction of impulses along nerve and muscle fibers (56, 55) has been described in detail elsewhere. 

The mechanism of the inhibition of acetylcholinesterase by physostigmine is related to the more general problem of the nature and mode of action of the active site (or sites) of the acetylcholinesterase molecule. 

Compound (258) was reported to be 190 times more potent than physostigmine against acetylcholinesterase, and it was 60 times more selective for inhibition of acetylcholinesterase than for butyrylcholinesterase (323). 

Anticholinesterases are agents that inhibit the enzyme acetylcholinesterase (AChE) and other cholinesterases that degrade acetylcholine (ACh). The hrst known anticholinesterase agent was Calabar bean, known as ordeal poison or ordeal bean its active ingredient is the carbamate compound physostigmine (Koelle 1975). It is thought that the Calabar bean was used by native tribesmen of Western Africa who used it in witchcraft rituals. The principle behind its use was that if a tribal member was accused of a capital crime, he or she would be subjected to a trial by ordeal in which they were forced to eat Calabar beans. If a person was innocent, he or she would quickly eat the beans with little apprehension, which would quickly induce... 

Enantiomeric comparison of the physiological activities of natural (-) and unnatural (-H) enantiomers of physostigmine (1) together with related compounds has also been investigated by Brossi and co-workers (57). It was found that unnatural (-H)-l inhibits acetylcholinesterase from electric eel considerably less than natural (-)-l, but the unnatural antipode exhibits lower toxicity (57) and blocks the open channel of the nicotinic... 

Acetylcholinesterase (AChE) inhibitors are successfully used as drugs for the treatment of Alzheimer s disease. Physostigmine, also named eserine, has been isolated from the Calabar bean Physostigmina Venenosum). It is classified as a pseudo-irreversible inhibitor because it reacts with acetyl- as well as butyryl-cholinesterase (BChE) to form a carbamylated serine which is hydrolyzed again with a fi/2 of 40 min [73]. Physostigmine inhibits AChE with an IC50 of 27.9 nM and BChE with an IC50 of 16 nM. Its enantiomer is 350 times less active on AChE and 150 times less active on BchE [74]. 

The carbaisosteres are as potent as or even more potent than the corresponding physostigmines. In addition, the (-)-enantiomers which possess the same absolute configuration at Csa and Cga as that of physostigmine are generally 6 to 12 times more potent in inhibiting acetylcholinesterase than the corresponding (-i-)-enantiomers. 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

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