G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations.

Previously reported pharmacological studies using the imidazole-containing histamine H3 receptor ligands GT-2331 (Cipralisant) and proxyfan resulted in a range of classifications (antagonist, agonist, and protean) for these compounds. We examined the role that the signaling system, with particular emphasis on the type of G protein, had on the pharmacology observed for H3 ligands. Ligands were assessed using assays measuring neurotransmitter release, cAMP, and guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding.

Species-related pharmacological heterogeneity of histamine H(3) receptors.

We compared radioligand binding and functional data for histamine H(3) receptor ligands across different tissues or species to evaluate the basis for pharmacological evidence of receptor heterogeneity previously reported. Agonist binding affinities showed correlation coefficients near unity in comparing human, dog, rat, and guinea pig cerebral cortical histamine H(3) receptors. Antagonist binding affinities revealed lower correlations for human compared to dog, rat, or guinea pig, suggesting species-based pharmacological differences.