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CELLULAR AND MOLECULAR

Probing Ligand-Specific Histamine H₁- and H₂-Receptor Conformations with N^G-Acylated Imidazolylpropylguanidines

High Throughput Screening Laboratory, The University of Kansas, Lawrence, Kansas (S.-X.X., Q.-Z.Y.); Departments of Medicinal Chemistry II (P.G., A.B.) and Pharmacology and Toxicology (R.S.), University of Regensburg, Regensburg, Germany; and Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, Kansas (R.S.)

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

Address correspondence to: Dr. Roland Seifert, Department of Pharmacology and Toxicology, University of Regensburg, Universitätsstrapße 31, D-93053 Regensburg, Germany. E-mail: roland.seifert{at}chemie.uni-regensburg.de

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