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

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 H(1)-, H(2)- and H(3)-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 H(1)-histamine receptors with comparable affinity (around 10(-5)M). BH and its metabolite AEP both interacted with the H(3)-histamine receptors, with microM affinity. HEP still showed some affinity for the H(3)-receptors but with a K(i)only 1/50 that of the parent compound. Histamine showed 10(-8)M affinity for the H(3)-receptor sites and was the only ligand to interact with H(2)-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 H(1)- and H(3)-binding sites and for AEP against H(3)-sites, indicating that these interactions take place in the absence of cooperativity. Histamine and HEP interacted with H(1)- and H(3)-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. Copyright 2001 Academic Press.