Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents

Abstract

In order to clarify the interaction of betahistine (BH) and its metabolites [aminoethylpyridine (AEP) and hydroxyethylpyridine (HEP)] for receptors that mediate the physio-pharmacological activities of histamine, we performed in vitro competition binding studies to obtain their binding affinity profile for H1-, H2- and H3-histamine receptors prepared from rodent brains. Crude synaptosomal membranes were incubated in the absence (total binding) or presence of the unlabelled ligands used to saturate the specific binding, or with different concentrations of BH, AEP or HEP. Receptor binding methods were validated by running known standard drugs together with the test compounds. Like histamine, only BH interacted with H1-histamine receptors with comparable affinity (around 10−5M). BH and its metabolite AEP both interacted with the H3-histamine receptors, with μ M affinity. HEP still showed some affinity for the H3-receptors but with aKi only 1/50 that of the parent compound. Histamine showed 10−8M affinity for the H3-receptor sites and was the only ligand to interact with H2-histamine receptors, all the others giving affinities above the mM range. Hill coefficients (as slopes of the sigmoidal inhibition isotherms) were close to unity for BH against H1- and H3-binding sites and for AEP against H3-sites, indicating that these interactions take place in the absence of cooperativity. Histamine and HEP interacted with H1- and H3-receptors with a Hill coefficient less than unity for the former and higher than unity for the latter (presence of negative and positive cooperativity, respectively). The results suggest that BH and its metabolites may act as neurotransmitter modulators of the histaminergic system.