Jpn. J. Pharmacol. 69, 75-82 (1995)

Structure-activity relationships of alkylxanthines: Alkyl chain elongation at the N1- or N7-position decreases cardiotonic activity in the isolated guinea pig heart

Fujiko Sanae (1), Shinji Ohmae (1), Mariko Kurita (1), Hiroyuki Sawanishi (2), Kenzo Takagi (3) and Ken-ichi Miyamoto (1,*)

Departments of (1) Applied Pharmacology and (2) Synthetic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-11, Japan
(3) 2nd Department of Internal Medicine, Nagoya University School of Medicine, Showa-ku, Nagoya 466, Japan
(*) To whom correspondence should be addressed.

Abstract: Relationships between the alkyl substitutions (C1-C6) and cardiac inotropic activities of xanthine derivatives were studied in isolated guinea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elongation of alkyl chain at the N3-position but decreased by substitution of a long alkyl group at the N1- or N7-position of the xanthine skeleton. Although positive inotropic activity in the right ventricular papillary muscle was also increased by longer alkyl groups at the N3-position, the inotropic activity became negative with an increment in alkyl chain length at the N1- or N7-position. The positive inotropic activity of alkylxanthines was correlated with their inhibitory activity on the phosphodiesterase (PDE) III isoenzyme. Adenosine A1 antagonism and PDE IV inhibitory activity were also partly associated with the inotropic activity because H-89, an inhibitor of cyclic AMP-dependent protein kinase, diminished the positive inotropic action and potentiated the negative inotropic action. These results indicate that the positive 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 elucidated from their cyclic AMP-dependent action.

Keywords: Structure-activity relationship, Alkylxanthine, Cardiac inotropic activity, Phosphodiesterase isoenzyme, Adenosine

Copyright© The Japanese Pharmacological Society 1995

[Back to TOC]