The agonist molecule, histamine, has been used as a starting point for the design of potential H2-receptor antagonists. Converting the side-chain amino group into a guanidine yielded the first histamine H2-receptor antagonist, Nalpha-guanylhistamine. Antagonism of H2 receptors was demonstrated by the inhibition of histamine-stimulated gastric acid secretion in the rat at high dose levels (approximate ID50 800 MUmol/kg, iv) and by the inhibition of histamine-stimulated tachycardia of guinea-pig right atrium (pA2 equals 3.9). Guanylhistamine behaves as a partial agonist at histamine H2 receptors.