TY - JOUR
T1 - Caffeine and theophylline analogues
T2 - Correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors
AU - Choi, Oksoon H.
AU - Shamim, Mah T.
AU - Padgett, William L.
AU - Daly, John W.
N1 - Funding Information:
One of the authors (M.T.S) was supported by a grant from the International Life Science Institute, Washington, D.C. The technical assistance of Marisa De La Cruz and Lisa M. Minasian, the latter sponsored by the Armenian assembly, is gratefully acknowledged.
Funding Information:
Materials: [3H]N6-Phenylisopropyladenosine (L3H]PIA, 38.5 Ci/mmol) and [2,8-3H]cyclic AMP (36.1 Ci/mmol) were from New England Nuclear, Boston, MA. 1,7-Dimethyl-3-propargylxanthine, 1,3,7_tripropargylxanthine and enprofylline were provided by Dr. John Neumeyer, Research Biochemicals, Wayland, MA and were prepared under NIH grant SBIR lR43AM37728-01. Nb - Cyclohexyladenosine and caffeine were from Sigma Chemical Co., St. Louis, MO; 3-isobutyl-1-methylxanthine from Aldrich Chemical Co., Milwaukee, WI; theophylline from Calbiochem, La Jolla, CA; and rolipram from Schering AG, Berlin. Synthesis of other xanthines has been described (7).
PY - 1988
Y1 - 1988
N2 - 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.
AB - 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.
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U2 - 10.1016/0024-3205(88)90517-6
DO - 10.1016/0024-3205(88)90517-6
M3 - Article
C2 - 2456442
AN - SCOPUS:0023888871
SN - 0024-3205
VL - 43
SP - 387
EP - 398
JO - Life Sciences
JF - Life Sciences
IS - 5
ER -