Correlation Between Hydrophobicity of N-Alkylxanthine Derivatives and their Biological Activities on Guinea-pig Isolated Tracheal Smooth Muscle

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Abstract
— Cyclic (c) AMP phosphodiesterase (PDE) inhibitory activities of N‐alkylxanthine derivatives (3‐methyl‐, 3‐ethyl‐, 3‐propyl‐, 3‐butyl‐, 1,3‐dimethyl‐, 1‐methyl‐3‐ethyl‐, 1‐methyl‐3‐propyl‐and 1‐methyl‐3‐butyl xanthines) and their relaxant effects on carbachol‐induced contraction and on resting tone guinea‐pig isolated tracheal smooth muscle have been investigated. The PDE inhibition constant (Ki) and the concentration producing 50% tracheal smooth muscle relaxation in‐vitro (EC50) were determined. Significant correlations between the ‐log Ki values and the ‐log EC50 values on the carbachol‐induced contraction or on the resting tone were found (r = 0·902 and 0·892). The apparent partition coefficient (P) between n‐octanol and pH 7·4 phosphate‐buffered saline (PBS) was measured as an index of hydrophobicity of the xanthine derivatives. There were significant correlations between log P and both ‐log EC50 values and between the log P and ‐log Ki values. These findings suggest that the cAMP PDE inhibitory activity of N‐alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.