For a series of 2-(pyridin-2-ylbutylamino)-5-(3-picolinylmethyl)pyrimidin- 4(1H)-ones (isocytosines) substituted in the pyridine 3-position, activity as H1- and H2-receptor histamine antagonists appears to correlate with the size of the 3-substituent. Steric interaction between the substituent and the butyl chain is explored by conformational analysis using Molecular Mechanics and Molecular Orbital calculations on 2-propyl- and 2-propyl-3-methyl-pyridines; it appears that the substituent may alter activity by changing the preferred conformation of the drug. This observation is extended by synthesis of a semirigid bicyclic analogue wherein 3-methylpyridinylbutyl is replaced by tetrahydroquinolinylpropyl. This compound is 2-3 times more potent as an H1-receptor antagonist confirming that a trans/trans conformation favours activity. Although derived from an H2-antagonist structure, the compound is not an antagonist at histamine H2 receptors thus proving that the conformational requirements are different at H1 and H2 receptors.