Abstract

Impromidine (IMP) and arpromidine (ARP)-derived guanidines are more potent and efficacious guinea pig (gp) histamine H₂-receptor (gpH₂R) than human (h) H₂R agonists and histamine H₁-receptor (H₁R) antagonists with preference for hH₁R relative to gpH₁R. We examined N^G-acylated imidazolylpropylguanidines (AIPGs), which are less basic than guanidines, at hH₂R, gpH₂R, rat H₂R (rH₂R), hH₁R, and gpH₁R expressed in Sf9 cells as probes for ligand-specific receptor conformations. AIPGs were similarly potent H₂R agonists as the corresponding guanidines IMP and ARP, respectively. Exchange of pyridyl in ARP against phenyl increased AIPG potency 10-fold, yielding the most potent agonists at the hH₂R-G_sα fusion protein and gpH₂R-G_sα identified so far. Some AIPGs were similarly potent and efficacious at hH₂R-G_sα and gpH₂R-G_sα. AIPGs stabilized the ternary complex in hH₂R-G_sα and gpH₂R-G_sα differently than the corresponding guanidines. Guanidines, AIPGs, and small H₂R agonists exhibited distinct agonist properties at hH₂R, gpH₂R, and rH₂R measuring adenylyl cyclase activity. In contrast to ARP and IMP, AIPGs were partial H₁R agonists exhibiting higher efficacies at hH₁R than at gpH₁R. This is remarkable because, so far, all bulky H₁R agonists exhibited higher efficacies at gpH₁R than at hH₁R. Collectively, our data suggest that AIPGs stabilize different active conformations in hH₂R, gpH₂R, and rH₂R than guanidines and that, in contrast to guanidines, AIPGs are capable of stabilizing a partially active state of hH₁R.