Acetylcholinesterase inhibitors physostigmine

Simplification of the original lead compound is especially appropriate for natural substances. This approach, known as the disjunctive approach (see Chapter 16) consists of a molecular dissection that deletes functions, structural elements, or cycles. Classical examples of disjunctive approaches are found in the pruning of the acetylcholinesterase inhibitor physostigmine to yield neostigmine and, later one, rivastigmine (Figure 19.1) or the change from somatostatin to a simplified hexapeptide. ... 

Analysis of ACh in blood and CSF poses two obstacles—low concentrations (<20 pmol/ml) and very fast hydrolysis by esterase (Tsai, 2000). An acetylcholinesterase inhibitor such as physostigmine maybe added to artificial CSF used for the collection of microdialysates to help overcome this problem (Kato et al., 1996). 

Another use for acetylcholinesterase inhibitors is in glaucoma, in which high intraocular pressure can lead to permanent damage to the optic disk, resulting in blindness. The local instillation of physostigmine (8.14) or echothiophate (8.19) solution in the eye results in a long-lasting decrease in the intraocular pressure as well as myosis (contraction of the pupil). 

Physostigmine, an acetylcholinesterase inhibitor widely used in treatment of glaucoma. Compare with other carbamate esters (Box 12-E)... 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

The prototype carbarnate-derived acetylcholinesterase inhibitor is physostigmine (247), an alkaloid isolated from the seeds of the Calabar bean, Physostigma venenosum. Physostigmine exhibits equal inhibitory activity against acetylcholinesterase and butyrylcholinester-ase (308). 

Acetylcholinesterase inhibitors has been a productive approach in the design of insecticides starting with the phosphate esters such as malathion and continuing on to carbamate esters such as carbaryl. For the latter, leads came from two carbamate reversible cholinesterase inhibitors used in medicine, the natural product physostigmine and the synthetic derivative, neostigmine. 

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