Anticholinesterase activity of monoquaternary ammonium salts containing hydrophobic radicals

Autor: I. I. Bityukova, V. M. Solov'ev, D. A. Kharkevich, N. V. Klimova, N. D. Igumnova, A. P. Skoldinov
Rok vydání: 1988
Předmět:
Zdroj: Pharmaceutical Chemistry Journal. 22:452-456
ISSN: 1573-9031
0091-150X
Popis: In connection with the existence of common features in the structures of the active sites of choline receptors and acetylcholinesterase (ACE), there is considerable interest in elucidating how the hydrophobicity of the radicals attached to the quaternary nitrogen atom affects the anticholinestaerase activity (for a discussion of the significance of the structures of cationic sites to anticholinesterase activity see [9]). First of all, we studied a series of tetramethylammonium derivatives in which one of the methyl groups was replaced by cyclic radicals having different degrees of hydrophobicity (R = cyelohexy!, phenyl, I- or 2-adamantyl). For comparison, the anticholinesterase activities of salts of the corresponding amines RNH2.HCI were determined. All of the studied ammonium salts are typical reversible inhibitors since the inhibition of ACE by these compounds does not depend on the time of incubation with the enzyme and occurs at once following the addition of inhibitor to an enzyme-substrate system. In Table i data which were obtained by studying the effects of ammonium salts on the rates of hydrolysis of acetylcholine by ACE are presented. The majority of the compounds studied (I-VI, VlI-XII) did not affect the maximum rate of hydrolysis (Vma x) of acetylcholine by ACE, and the sole effect observed in their presence was an increase of K M (Michaelis constant), which indicates that these compounds are classical competitive-type inhibitors. On the other hand, compounds XV and XVI reduce the maximum rate of hydrolysis of acetylcholine but do not affect KM, i.e., these behave as classical noncompetitive inhibitors. The inhibition of acetylcholine hydrolysis by compounds VII and XIV is accompanied by an increase in K M and a reduction of Vma x, which is typical of mixed-type inhibition. As characteristics of the reactivities of reversible inhibitors we have presented the values of the inhibition constants K i, which are indicative of the binding strength between the inhibitor and the enzyme. It follows from Table i that the anticholinesterase activity is influenced by the volume and hydrophobicity (which varies in a parallel fashion with the number of carbon atoms) of the carbohydrate radicals attached to the quaternary nitrogen atom. Replacement of one of the methyl groups in the tetramethylammonium salt by a cyclohexyl group (compound IV) raises the hydrophobicity of the compound to the level of that of the tetraethylannnonium salt II and thus results in the two compounds having comparable inhibition constants. It is noteworthy that the phenyltrimethylammonium salt VI has greater anticholinesterase activity than salt IV (the inhibition constant is a factor of 7 lower) in spite of the fact that the hydrophobicities of the two compounds are close to one another. This may be the result of additional ionic interactions due to partial charges arising in the substituted phenyl ring. Further increases in the hydrophobicities of the substituted ammonium salts studied brought about by introduction of the bornyl radical (compound IX) or, having approximately the same hydrophobicity, the i- or 2-adamantyl radicals (compounds XI or XIII) did not substantially affect the anticholinesterase activity, possibly due to certain features of these compounds'
Databáze: OpenAIRE
Externí odkaz: