STRUCTURE-ACTIVITY-RELATIONSHIPS OF ALKYLXANTHINES - ALKYL CHAIN ELONGATION AT THE N1-POSITION OR N7-POSITION DECREASES CARDIOTONIC ACTIVITY IN THE ISOLATED GUINEA-PIG HEART

Relationships between the alkyl substitutions (C-1-C-6) and cardiac in otropic activities of xanthine derivatives were studied in isolated gu inea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elo ngation of alkyl chain at the N3-position but decreased by substitutio n of a long alkyl group at the N1- or N7-position of the xanthine skel eton. Although positive inotropic activity in the right ventricular pa pillary muscle was also increased by longer alkyl groups at the N3-pos ition, the inotropic activity became negative with an increment in alk yl chain length at the N1- or N7-position. The positive inotropic acti vity of alkylxanthines was correlated with their inhibitory activity o n the phosphodiesterase (PDE) III isoenzyme. Adenosine A(1) antagonism and PDE IV inhibitory activity were also partly associated with the i notropic activity because H-89, an inhibitor of cyclic AMP-dependent p rotein kinase, diminished the positive inotropic action and potentiate d the negative inotropic action. These results indicate that the posit ive inotropic activity of alkylxanthines becomes weak with elongation of alkyl chains at the N1- and N7-positions; In particular, xanthines having two long alkyl chains show a negative inotropic activity on the right ventricular papillary muscle, an effect that could not be eluci dated from their cyclic AMP-dependent action.