Probing Ligand-Specific Histamine H1- and H2-Receptor
Conformations with NG-Acylated Imidazolylpropylguanidines

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 NG-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-Gs fusion protein and gpH2R-Gs identified so far. Some AIPGs were similarly potent and efficacious at hH2R-Gs and gpH2R-Gs. AIPGs stabilized the ternary complex in hH2R-Gs and gpH2R-Gs 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.