Monoamine Oxidase Inhibitory Drugs Research Articles

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Use of spectral mapping technique for the separation of solvent strength and selectivity on β-cyclodextrin polymer-coated HPLC column using monoamine oxidase inhibitory drugs as solutes

Spectral mapping technique has been used for the separation of the strength and selectivity of retention of 17 monoamine oxidase inhibitory drugs and 5 organic modifiers on a β-cyclodextrin polymer-coated silica column (βCDP). The potency values of the spectral maps were considered as indicators of the capacity of drugs to bind to the βCDP surface and the capacity of organic modifiers to remove the drugs from the surface. The multidimensional selectivity map were visualized by the two-dimensional nonlinear mapping technique. Stepwise regression analysis established that both the steric dimensions and hydrophobicity of drugs influence the strength and selectivity of their binding to βCDP whereas the selectivity of organic modifiers depended on the bulkiness of the molecule. The data suggest that the interaction of drugs and organic modifiers with the surface of the βCDP support depends on their capacity to fit sterically in the βCDP cavity and the strength of the hydrophobic forces between the apolar inner wall of the cyclodextrin cavity and the substructures of guest molecules inserted in the cavity.

Effect of physiochemical parameters on the retention of some monoamine oxidase inhibitory drugs on a porous graphitized carbon column

The retention of sixteen monoamine oxidase inhibitory drugs (proparlgylamine derivatives) was determined on a porous graphitized carbon (PGC) column using ethanol-water mixtures as eluents. The HPLC retention characteristics of drugs were correlated with their physicochemical properties using stepwise regression analysis and principal component (PC) analysis. The dimensions of the matrices for PC loadings and variables was reduced using a non-linear mapping technique, varimax rotation and cluster analysis. It has been established that the drugs can be well separated on the PGC column in ethanol-water eluents. Calculations proved that the retention behavior of monoamine oxidase drugs on PGC column is of mixed character: both steric and electronic parameters influence the retention.

Use of principal component analysis for the evaluation of the retention behaviour of monoamine oxidase inhibitory drugs on β-cyclodextrin column

The retention of 17 monoamine oxidase inhibitory drugs (proparlgylamine derivatives) were determined on a β-cyclodextrin polymer (βCDP)-coated silica column using ethanol-0.05 M K 2HPO 4 (6:4 v/v) as the eluent. The relative strength of interaction between the drugs and a water soluble β-cycodextrin polymer was determined by charge-transfer chromatography carried out on reversed-phase TLC layers. The relationship between capacity factors, physicochemical parameters and inclusion complex forming capacity of the monoamine oxidase inhibitory drugs were evaluated by stepwise regrerssion analysis and by principal component analysis (PCA) followed by two-dimensional nonlinear mapping and varimax rotation. Calculations indicated that the retention of monoamine oxidase inhibitory drugs on βCDP column is mainly governed by their steric and lipophylic parameters. Significant linear correlations were found between the corresponding coordinates of varimax rotation and two-dimensional nonlinear maps proving the suitability of both methods for the reduction of dimensionality of complicated data matrices.

Comparison of Various Multivariate Mathematical-Statistical Methods for the Evaluation of the Retention Behaviour of β-Cyclodextrin Polymer Coated Silica Column

Abstract The retention of 17 monoamine oxidase inhibitory drugs was determined on a β-cyclodextrin polymer (βCDP)-coated silica column using acetonitrile - 0.05 M K2HPO4 eluent. The relationship between retention capacity and the physicochemical parameters of solutes determined with various adsorptive and reversed-phase TLC methods was evaluated by principal component analysis followed by two-dimensional non-linear mapping, vari-max rotation around two axes and cluster analysis. The HPLC and TLC retention parameters of the drugs were widely separated on the two dimensional nonlinear map of principal component loadings indicating the unique retention characteristics of βCDP column. Significant linear correlations were found between the rotated principal component loadings and the coordinates of their two-dimensional non-linear map. The better separation of variables on the two dimensional maps suggested that the principal analysis followed by two-dimensional non-linear mapping or by varimax rotation is a m...

Correlation between Monoamino Oxidase Inhibitor Activity of Some Thiazol-2-ylhydrazines and Their Interaction with Dipalmitoylphosphatidylcholine Liposomes

A calorimetric investigation has been carried out on the influence exerted by some 1-(alkoxybenzoyl)-2-{4-substituted thiazolyl- 2-yl)hydrazines, possessing monoamine oxidase inhibitory (MAOI) activity, on the thermotropic behavior of model membranes constituted by dipalmitoylphosphatidylcholine (DPPC) vesicles. Attention was paid to evaluate how structural variations of drugs may influence drug-lipid interaction. The examined drugs were found to modify the gel to liquid-crystal phase transition of DPPC liposomes, by causing a shift of the transition temperature (Tm) toward lower values and a negligible variation in the enthalpy changes (△H). The different effects on DPPC thermotropic behavior of these MAOI drugs could be considered in terms of different substituents on the molecule’s backbone. The calorimetric results were related to drug’s MAO inhibitory activity measured by fluorescence techniques and the apparent distribution coefficient of the compounds in water/n-octanol. A hypothesis on a correlation between a drug’s structure, Inhibitory activity, and membrane interaction has been suggested.

Retention of some monoamine oxidase inhibitory drugs on a β-cyclodextrin polymer-coated silica column

The retention of seventeen monoamine oxidase inhibitory drugs (mono- and disubstituted derivatives of propargylamine) was determined on a β- cyclodextrin polymer (β-CDP)-coated silica column using methanol-0.05 M K 2HPO 4 (6:4, v/v) as the eluent. The inclusion complex formation between the drugs and a water-soluble β-cyclodextrin polymer was studied by charge-transfer chromatography carried out on reversed- phase TLC layers. The capacity factors were correlated with the various physico-chemical parameters and with the inclusion complex-forming capacity of the monoamine oxidase inhibitory drugs. Calculations indicated that the inclusion complex-forming capacity of the drugs does not influence their retention on a β-CDP column, that is, the water-soluble and water-insoluble β-CDPs show different retention characteristics. The specific hydrophilic adsorption surface of the solutes significantly influences the retention in HPLC. The results suggest that the selectivity of the β-CDP-coated silica support may be different from that of the traditional alkyl-bonded reversed-phase columns.

Interaction of monoamine oxidase inhibitory drugs with some phospholipids

The effect of 17 monoamine oxidase inhibitory drugs (propargylamine derivatives) on the phase transition parameters of some synthetic phospholipids has been studied by differential scanning calorimetry. The drugs modified the thermal behaviour of phospholipids proving the existence of phospholipid—drug interactions. Phosphatidylethanolamine, phosphatidylcholine and phosphatidic acid equally interact with the monoamine oxidase inhibitory drugs. Significant correlations were found between the change of the phase transition parameters of phospholipids and the hydrophilic and hydrophobic molecular parameters of drugs. Calculations suggest that both hydrophilic (between the head group of phospholipids and the polar propargylamine group of drugs) and hydrophobic (between the apolar fatty acid chains of phospholipids and the lipophilic substructures of drugs) forces are involved in the phospholipid—drug interaction. Chloro substitution in the hydrophobic moiety of drugs enhances considerably the strength of interaction.

Lipophilicity Determination of Some Monoamine Oxidase Inhibitors by Reversed-Phase Thin-Layer Chromatography. The Effect of pH

Abstract The lipophilicity (RM value) of 17 monoamine oxidase inhibitory drugs was determined by reversed-phase thin-layer chromatography and the effect of various eluent additives such as acetic acid, sodiumacetate and sodium chloride on the retention was studied. Each drug exhibited regular retention behavior, their RM value linearly decreased with the increasing concentration of methanol in the eluent. Acetic acid decreased the retention, the effect was higher at lower acid concentrations which indicates that the phenomena is of saturation character. The effect of sodiumchloride and sodiumacetate was negligible. The lipophilicity and specific hydrophobic surface area values of the drugs were intercorrelated, however, their information content is different, therefore their simultaneous application in quantitative structure-activity relationship studies is recommended.

Porous graphitized carbon and octadecylsilica columns in the separation of some monoamine oxidase inhibitory drugs

The retentions of seventeen monoamine oxidase inhibitory drugs (propargylamine derivatives were determined on a porous graphitized carbon (PGC) column using unbuffered methanol-water and acetonitrile-water eluents and on an octadecylsilica column with methanol-water eluents using constant and varying buffer concentrations. Principal component analysis showed that the retention characteristics of the PGC and octadecylsilica columns differ considerably. A marked deviation between the selectivities of methanol and acetonitrile organic modifiers was observed on PGC. The buffer concentration has a significant impact on the retention of drugs on the octadecylsilica column. The type of substitution (heterocyclic, condensed ring, substituted benzene) accounts for the retention differences irrespective of the type of column, eluent and buffer concentration.

Use of TLC and multivariate mathematical statistical methods to study the interaction of monoamine oxidase inhibitory drugs with amino acids

The interaction of 17 monoamine oxidase inhibitory drugs (propargylamine derivatives) with amino acids was studied by charge-transfer chromatography. The data set was evaluated by principal component analysis (PCA). To assess the effect of the information loss caused by normalization, PCA was separately carried out on the covariance and on the correlation matrix. The strength and selectivity of interaction was separated by the spectral mapping technique. Calculation proved that the amino group of the drugs interacted with the second car☐yl group of dicar☐ylic amino acids, and that the interaction was of electrostatic character. This finding made probable the direct interaction between the drugs and the target enzyme or enzymes. The results of both PCA methods were similar. However, coordinates of the spectral map showed only slight correlation with the corresponding coordinates of the two-dimensional nonlinear maps proving the different information content of the methods.

Lipophilicity determination of some monoamine oxidase inhibitors: the effect of methanol and ammonium chloride

The lipophilicity ( R M value) of seventeen monoamine oxidase inhibitory drugs was determined by reversed-phase thin-layer chromatography, and the effect of salt concentration on the reversed-phase retention was studied by adding ammonium chloride to the eluent. Each drug exhibited regular retention behaviour, its R M value linearly decreasing with increasing concentration of methanol in the eluent. Ammonium chloride decreased the retention: the effect was higher at lower salt concentrations, which indicates that the phenomenon is of saturation character. The influence of ammonium chloride depended on the concentration of methanol (on the dielectric constant of the eluent) suggesting that methanol suppresses the dissociation of ammonium chloride resulting in a modified salting-in effect.

Relationship between the hydrophobic and hydrophilic molecular parameters of some monoamine oxidase inhibitory drugs, determined by means of adsorptive and reversed-phase thin-layer chromatography

The absorption capacity, the specific hydrophilic surface area, the lipophilicity and the specific hydrophobic surface area of 17 monoamine oxidase inhibitory drugs were determined by means of adsorptive and reversed-phase thin-layer chromotography for future application of these molecular parameters in quantitative structure-activity relationship studies. Principal component analysis suggests that most of the physicochemical parameters have a different information content, and their application in the elucidation of their mode of action is therefore justified.

A simple method for screening Monoamine Oxidase (MAO) inhibitory drugs for type preference

A simple method is described for screening monoamine oxidase (MAO) inhibitors for preferential action on either type A or type B MAO. Kynuramine, a substrate for both types of MAO, was used and the sources of enzyme were rat heart (type A) and mouse heart (type B). The method clearly showed that clorgyline (a preferential type A inhibitor) preferentially inhibited rat heart MAO; whereas pargyline (a preferential type B inhibitor) preferentially inhibited mouse heart MAO. Pheniprazine, an inhibitor without type preference, was equally effective in the two tissues. The method was used to substantiate a report by others that amphetamine has preferential inhibitory action against type A MAO.