The histamine H2-antagonist properties of propantheline and its tertiary amine derivatives were investigated. Propantheline and methantheline inhibited the histamine-activated cyclase of guinea-pig brain homogenates, a well characterized H2-receptor preparation; the inhibition was not competitive. Tertiary amine derivatives were competitive H2-antagonist in this system, one such derivative exhibiting greater potency than cimetidine. In concentrations blocking the brain H2-receptors, these derivatives had no effect on atrial histamine dose-response curves, but evidence for their antagonism on peripheral H2-receptors was obtained with papillary muscle preparations. The results suggest that the guinea-pig brain H2-linked cyclase of homogenates is a sensitive predictor of peripheral H2-antagonist activity. These drugs may also be effective inhibitors of gastric secretion.