Derivatives of lupinin and epilupinin as ligands of various cholinesterases

Literature data have been summarized on interaction of cholinesterases of some mammals and arthropods with a group of isomer derivatives of alkaloid lupini and its epimer epilupinin. As substrates of cholinesterases of several mammals there are studied 8 acetates containing in their molecules the chinolysidin bicycle with different structure of N-alkyl radical, which showed certain elements of specificity of action. For 2 isomer esters that are derivatives of the protonated base of the lupinin and epilupinin structures, differences in their substrate characteristics were revealed. The polyenzyme analysis if anticholinesterase efficiency was performed for 30 organophosphorus inhibitors that are dialkoxyphosphorus derivatives of lupinin and epilupinin; as a result, quite a few peculiarities of their action depending on their structure were revealed. Several tested compounds turned out to act as specific inhibitors of cholinesterases of some mammals and arthropods.     

Effect of the substrate structure on the mechanism of reversible inhibition of cholinesterases of different origin

The mechanism of reversible inhibition of human erythrocyte acetylcholinesterase, horse blood serum butyrylcholinesterase, cholinesterase from optical ganglia of the squids, PacificTodarodes pacificus and CommodoreBerryteuthis magister, from different zones of habitation area is studied in the presence of substrates of various structures (acetylcholine, butyrylcholine, acetylthiocholine, butyrylthiocholine, phenylacetate, indophenylacetate, 2,6-dichlorophenylindophenylacetate). Tested as reversible inhibitors were tetramethylammonium iodide, tetraethylammonium iodide, choline iodide, and two derivatives of α,ω-bis(trimethylammoniommethyl)oligodimethylsiloxane dichloride. It has been revealed that the mechanism of the reversible anticholinesterase action depends essentially both on the enzyme nature and on the structures of substrate and inhibitor. The transfer from cation-containing to hydrophobic substrates increased essentially the contribution of uncompetitive component of the inhibitory constant. In the presence of butyric acid esters (butyrylcholine, butyrylthiocholine), the potency of inhibitors was lower than at hydrolysis of the corresponding acetates. The effect of the substrate structure on the mechanism of reversible inhibition was revealed to a greater extent in reactions with participation of squid cholinesterases.     

Investigation of cholinesterases of different origin by the method of inhibitor analysis (variation of structure of phosphoryl part of alkoxyalkylthiophosphonates)

Analytical review of literature data is carried out on inhibitor analysis of structure of cholinesterases in various animals (vertebrates, insects, and molluscs) by studying their interaction with 68 alkoxyalkylthiophosphonates of 10 homologous series with regularly changed structure of phosphoryl part. The presented data are discussed in the comparative-enzymological aspect of current concepts of structure of active center of cholinesterases.     

Alkylammonium chlorobenzoates are a new group of ester-containing reversible inhibitors of cholinesterases of different animals

Interaction with cholinesterases (ChEs) of nine specially synthesized derivatives of dimethylaminoalkyl esters of 2-chloro-and 2,4-dichlorobenzoic acids and their iodoalkylates is studied. Used as enzyme sources were partially purified preparations of acetylcholinesterase (AChE) from human erythrocytes and butyrylcholinesterase (BChE) from horse blood serum, as well as water homogenates of the frog Rana temporaria brain and of the Pacific squid Todarodes pacificus optical ganglia. The studied benzoates failed to be hydrolyzed by the studied ChEs at the enzyme concentrations exceeding 10 times those used for determination of the acetylthiocholine hydrolysis rate. These compounds have turned out to be reversible inhibitors of ChEs of the mixed-noncompetitive type of action. Effects on the anticholinesterase activity of such structural elements of the inhibitors as the acidic part of the benzoate molecule, length of polymethylene chain in the molecule alcoholic part, and the structure of ammonium group are studied. This study has allowed revealing some peculiarities of the reaction capability of vertebrate and invertebrate ChEs.     

Interaction of reversible inhibitors with the cholinesterase of the squid Berryteuthis magister from different areas of the Bering Sea

Studies have been made of the interaction of 13 onium reversible inhibitors with cholinesterase from the visual ganglia of the squid B. magister from various habitats (Kurile Islands, Olyutorsk-Navarin and Navarin-Alaskan regions). In some of the cases, differences were found between the enzymes from various specimens with respect to values of the generalized inhibitor constant (which is a measure of inhibitor effectiveness) and the pattern of inhibition. These data reveal intraspecific polymorphism in B. magister from the Bering Sea.