Analogues of tetramethylpyrazine affect membrane fluidity of liposomes: relationship to their biological activities
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abstract
Several structurally similar pyrazine derivatives, tetramethylpyrazine, triethylpyrazine and tetraethylpyrazine have previously been found to inhibit a broad spectrum of plasmalemma-associated biological activities of various tissues, including ion channels and membrane receptors in a given order of potency that increases with increasing bulkiness and hydrophobicity of these drugs. Our earlier speculation that the multiple membrane effects elicited by these pyrazine derivatives were associated with changes in the bulk physical properties of the biological membranes in the presence of these drugs was confirmed by fluorescence polarization and electron spin resonance studies. Since biological membranes contain a complicated mixture of a large variety of lipids and proteins, we chose to study the molecular properties of the interaction of these three pyrazine derivatives using a simple model system composed of synthetic phospholipids. We measured the effects of the drugs on the fluidity (or microviscosity) of these model membranes, as well as determining the phase-transition properties of the model membranes with the use of fluorescence polarization, electron spin resonance and differential scanning calorimetry. All the methods employed yielded qualitatively similar results. Tetramethylpyrazine, the smallest and the least hydrophobic amongst these three drugs, had minimal or no effect on the phase-transition of phospholipids based on temperature dependence studies, whereas tetraethylpyrazine, the largest and the most hydrophobic of the three, elicited the most potent effect in a concentration-dependent manner. These results could be attributed to the amount of incorporation of these pyrazine derivative into the liposomes, an interaction which occurs more favourably at temperatures above the gel to liquid crystalline phase-transition temperature.(ABSTRACT TRUNCATED AT 250 WORDS)
