Impromidine ( IMP) and arpromidine ( ARP)- derived guanidines are more potent and efficacious guinea pig ( gp) histamine H-2-receptor ( gpH(2)R) than human ( h) H2R agonists and histamine H-1- receptor ( H (1) R) antagonists with preference for hH(1)R relative to gpH(1)R. We examined N-G- acylated imidazolylpropylguani-dines ( AIPGs), which are less basic than guanidines, at hH(2)R, gpH(2)R, rat H2R ( rH(2) R), hH(1)R, and gpH(1)R 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 hH(2)R- G (S alpha) fusion protein and gpH(2)R- G(S alpha) identified so far. Some AIPGs were similarly potent and efficacious at hH2R-G(S alpha) and gpH(2)R-G(S alpha). AIPGs stabilized the ternary complex in hH(2)R-G(S alpha) and gpH(2)R-G(S alpha) differently than the corresponding guanidines. Guanidines, AIPGs, and small H2R agonists exhibited distinct agonist properties at hH(2)R, gpH(2)R, and rH(2)R measuring adenylyl cyclase activity. In contrast to ARP and IMP, AIPGs were partial H1R agonists exhibiting higher efficacies at hH(1)R than at gpH(1) R. This is remarkable because, so far, all bulky H 1 R agonists exhibited higher efficacies at gpH(1)R than at hH(1)R. Collectively, our data suggest that AIPGs stabilize different active conformations in hH(2) R, gpH(2)R, and rH(2)R than guanidines and that, in contrast to guanidines, AIPGs are capable of stabilizing a partially active state of hH(1)R.