title: 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 H(2)-receptor (gpH(2)R) than human (h) H(2)R 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 imidazolylpropylguanidines (AIPGs), which are less basic than guanidines, at hH(2)R, gpH(2)R, rat H(2)R (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 H(2)R 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(salpha) fusion protein and gpH(2)R-G(salpha) identified so far. Some AIPGs were similarly potent and efficacious at hH(2)R-G(salpha) and gpH(2)R-G(salpha). AIPGs stabilized the ternary complex in hH(2)R-G(salpha) and gpH(2)R-G(salpha) differently than the corresponding guanidines. Guanidines, AIPGs, and small H(2)R 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 H(1)R 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.
authors.affiliation: High Throughput Screening Laboratory, The University of Kansas, Lawrence, USA.
authors.forename: Sheng-Xue
authors.initials: SX
authors.lastname: Xie
authors.forename: Prasanta
authors.initials: P
authors.lastname: Ghorai
authors.forename: Qi-Zhuang
authors.initials: QZ
authors.lastname: Ye
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000215:Acylation; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000737:chemistry / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D015336:Molecular Probe Techniques; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism*; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D008024:Ligands; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2