Effects of Impromidine- and Arpromidine-Derived Guanidines on Recombinant Human and Guinea Pig Histamine H₁ and H₂ Receptors

Abstract

Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H₂ receptor (gpH₂R) than at the human H₂R (hH₂R) in the GTPase assay. Additionally, such guanidines are histamine H₁ receptor (H₁R) antagonists with preference for the human relative to the guinea pig receptor. The purpose of this study was to examine structure-activity relationships of guanidines at human and guinea pig H₁R and H₂R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H₂R and antagonistic activity at H₁R as assessed in the steady-state GTPase assay. Species selectivity of derivatives was similar as compared with the parent compounds. None of the structural modifications examined (different aromatic ring systems and different ring substituents) was superior in terms of H₂R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H₂R. Guanidines exhibited distinct structure-activity relationships for H₁R antagonism in a radioligand competition binding assay and the GTPase assay and for H₁R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH₂R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H₁R