The effects of the enantiomers of two chiral analogues of histamine (alpha, N alpha-dimethylhistamine and N alpha-methyl-alpha-chloromethylhistamine) were studied at H3-autoreceptors modulating histamine release in rat brain slices. These compounds act as H3-receptor agonists, displaying a low potency relative to histamine (below 4%) but a pronounced stereoselectivity (ratio of 31 for the isomers of alpha, N alpha-dimethylhistamine and 183 for their halogenated analogues) was observed. The (+)isomers (corresponding to S-configurated L-histidine) were highly preferred at H3-receptors, whereas the (-)isomers were more potent at H2-receptors, no difference being observed at H1-receptors. In addition, no such stereoselectivity was observed for the two isomers of a chiral impromidine derivative: both Sopromidine and its S enantiomer acted as antagonists of histamine at H3-autoreceptors with similar potencies (Ki = 5.6 X 10(-8) M and 4.5 X 10(-8) M), whereas Sopromidine acted as an H2-receptor agonist and the S-enantiomer as an H2-receptor antagonist. Our results indicate that H3-autoreceptors are chemically stereoselective, with structural requirements different from those of H1- and H2-receptors.