Acetylcholine analogs

Hydrolysis of activated esters of a-amino acids or acetylcholine analogs catalysed by Cu or Zn modified with the tenside ligands 118,119 and 120 (Table... 

In the October 10, 1988 issue of Chemical Engineering News there appeared a brief report from the Israel Institute for Biological Research about an acetylcholine analog, cis-2-methylspiro(1,3-oxathiolane-5,3 )quinuclidine, which seems to be very specific for brain Ach receptors involved in AD. In the same report another drug in Phase I clinical trials was mentioned. Produced by Bristol-Myers it is meant to be used for a variety of cognitive memory disorders including AD. 

Rogers GA, Parsons SM (1989) Inhibition of acetylcholine storage by acetylcholine analogs in vitro. Mol Pharmacol 36 333-341. 

It is important to determine whether or not each substituent parameter is an independent variable. If a considerable correlation exists between two parameters in a set of compounds, it is often difficult to evaluate the quality of structure—activity correlations. The data in Table II are for the muscarine-like activity of acetylcholine analogs measured by the blood pressure descent of cats (55). The effect of cationic head structure has been analyzed using physicochemical parameters of the N substituents (II). 

Table II. Muscarine-like Activity of Acetylcholine Analogs...

An alternative approach uses the distance geometry paradigm, in which all the constraints are combined to form the distance matrix from which energetically feasible conformations of the set of molecules are sought mathematically. Sheridan et al. (439) demonstrated this approach on acetylcholine analogs that are muscarinic agonists. Both of these approaches ask the same question and suffer from the same limitations, and differ only in computational technique. Each suffers from the local minima problem, in that each uses a... 

Ing (39) noted that the potencies of acetylcholine analogs containing charged atoms other than nitrogen (phosphorus, arsenic, sulfur) are in inverse order to the volumes occupied by these atoms. The carbon isostere (8) of acetylcholine exhibits no cholinergic activity, but it is an excellent substrate for acetylcholinesterase (42). Studies of the role of nitrogen substituents in the acetylcholine molecule indicate that the N,N,N-trimethy quaternary... 

The principle of conformational restriction was first applied to characterize the bioactive conformation of acetyl choline acting at the muscarinic and nicotinic receptors. Conformational restriction has been applied to many other small ligands (e.g. see reviews by Martin-Smith et al., Portogh-ese, Mutschler and Lambrecht, and Casy et but the work on acetylcholine analogs exemplifies the necessary ideas and techniques required to understand the general approach, as well as its strengths and limitations, when applied to small molecules. 

Anatoxin-a(S) can therefore be measured by its inhibition of acetylcholinesterase whose enzyme activity can be measured by several ways. One example is its degradation of the acetylcholine analog, acetylthiocholine, and subsequent measurement of the released thiocholine by the sulfur reacting chemical Ellman s reagent. Acetylcholinesterase has been cloned and its mutation can increase the enzyme s sensitivity for anatoxin-a(S). Combining different acetylcholinesterase mutants with divergent specificity for anatoxin-a(S) and the above-mentioned organophosphate insecticides has enabled better analyte discrimination. This multiple enzyme method has been implemented in a biosensor that carries several of the acetylcholinesterase mutants. 

FIGURE 153 Example of a chemical graph-based ealculation of molecular similarity, (a) Chemical graph of acetylcholine, (b) Chemical graph of an acetylcholine analog, (c) A common structure (CS) of (a) and (b). (d) The maximum common substructure (MCS) of... 

Active-Site Directed Molecules Related to Acetylcholine - In view of the widespread interest in compounds designed to form covalent bonds at or near the active sites to which they are attached 2, it is not surprising that there is considerable interest in the preparation of active-site directed acetylcholine analogs. Chlou and Sastry 3 have synthesized fluoro-, chloro-, bromo-, and lodoacetyl-chollne, as well as the dlmethylamlno analogs of these compounds. These compounds were found to be substrates of acetylcholinesterase with higher K s and lower affinities than those of acetylcholine. 

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