Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors

Life Sci. 1988;43(5):387-98. doi: 10.1016/0024-3205(88)90517-6.


The behavioral stimulant effects of xanthines, such as caffeine and theophylline, appear to involve blockade of central adenosine receptors. However, 3-isobutyl-1-methylxanthine (IBMX), a potent phosphodiesterase (PDE) inhibitor, produces behavioral depression. The effects of caffeine analogs on open field behavior of mice and potencies as antagonists of adenosine receptors and as inhibitors of three classes of brain PDE have been compared. 1,7-Dimethyl-3-propargylxanthine, 1,3,7-tripropargylxanthine, and 3,7-dimethyl-1-propargylxanthine, which have high affinity for adenosine receptors and weaker activity as PDE inhibitors, all increase behavioral activity. In contrast, 1,3,7-tripropylxanthine, a more potent inhibitor of the brain calcium-independent (Ca-indep) PDEs than 1,3,7-tripropargylxanthine, produces behavioral depression, even though both analogues are potent adenosine receptor antagonists. 7-Benzyl-IBMX, an active receptor antagonist and selective inhibitor of a brain calcium-dependent (Ca-dep) PDE, produces a slight behavioral activation. Xanthines that are potent adenosine receptor antagonists and relatively weak inhibitors of the Ca-indep PDEs reverse the depressant effects of N6-cyclohexyladenosine, while xanthines, such as 1,3,7-tripropylxanthine, that are potent inhibitors of the Ca-indep PDEs, do not. The results suggest that the behavioral effects of xanthines may be determined primarily by relative activity as adenosine receptor antagonists and as inhibitors of brain Ca-indep PDEs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Caffeine / analogs & derivatives*
  • Caffeine / pharmacology
  • Calcium / physiology
  • In Vitro Techniques
  • Male
  • Mice
  • Motor Activity / drug effects*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Purinergic / drug effects*
  • Structure-Activity Relationship
  • Theophylline / analogs & derivatives*
  • Theophylline / pharmacology


  • Phosphodiesterase Inhibitors
  • Receptors, Purinergic
  • Caffeine
  • Theophylline
  • Calcium
  • 1-Methyl-3-isobutylxanthine