A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: Effect of various substitutions at the primary amino function

Article abstract of DOI:10.1021/jm0504353

In an effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H₃ receptor (H₃R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H₃R and H₄R subtypes by radioligand displacement experiments and for their intrinsic H₃R activities via a CRE-mediated β-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H₃R antagonists identified within this series, compounds 2b and 2h display an H₃R affinity in the low nanomolar concentration range (pK_i values of 8.1 and 8.4, respectively). A very potent and selective H₃R agonist (11, pEC ₅₀ = 8.9, α = 0.94) and a very potent, though not highly selective, H₃R inverse agonist (2k, pIC₅₀ = 8.9, α = -0.97) have been identified as well.