Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H 2 receptor (gpH 2 R) than at the human H 2 R (hH 2 R) in the GTPase assay. Additionally, such guanidines are histamine H 1 receptor (H 1 R) 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 H 1 R and H 2 R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H 2 R and antagonistic activity at H 1 R 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 H 2 R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H 2 R. Guanidines exhibited distinct structure-activity relationships for H 1 R antagonism in a radioligand competition binding assay and the GTPase assay and for H 1 R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH 2 R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H 1 R.

Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H 2 receptor (gpH 2 R) than at the human H 2 R (hH 2 R) in the GTPase assay. Additionally, such guanidines are histamine H 1 receptor (H 1 R) 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 H 1 R and H 2 R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H 2 R and antagonistic activity at H 1 R 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 H 2 R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H 2 R. Guanidines exhibited distinct structure-activity relationships for H 1 R antagonism in a radioligand competition binding assay and the GTPase assay and for H 1 R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH 2 R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H 1 R.

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