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J Physiol. 1974 Nov;242(3):615-34.

Structure-activity relations for caffeine: a comparative study of the inotropic effects of the methylxanthines, imidazoles and related compounds on the frog's heart.


1. The ability of several groups of compounds, related to caffeine, to induce contractures in isolated frog auricular trabeculae has been tested.2. Of the methylxanthines, theophylline, theobromine and paraxanthine are of similar potency to caffeine. This applies to contractures produced in either high-potassium or in sodium-free solution, and to the twitch responses in normal Ringer.3. Xanthines in which the 9-position nitrogen is combined and is, therefore, without an ethylene bond do not affect contraction.4. The hypothesis is put forward that a double-bonded nitrogen, in an imidazole ring, is required for activity of the methylxanthine. This hypothesis is supported by the ability of imidazole and several close derivatives (e.g. histamine), as well as imidazolines, to evoke contractures. As predicted by the hypothesis, imidazolidines and imidazolidones, in which all the nitrogen atoms have single bonds, fail to initiate tension development.5. The activity of histamine and histidine is only demonstrable at high pH ( bumpy equals, equals 9.0).6. Raising the pH in sodium-free solution induces a transient contracture.7. Several arguments suggest that cyclic AMP is probably not an intermediate in the response to the methylxanthines. The activity of cyclic AMP (and adenosine) in eliciting contractures is predicted by the hypothesis because they contain an imidazole moiety as part of their molecular structure.

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