Abstract
Both the histamine H1-receptor (H1R) and H2-receptor (H2R) exhibit pronounced species selectivity in their pharmacological properties; i.e., bulky agonists possess higher potencies and efficacies at guinea pig (gp) than at the corresponding human (h) receptor isoforms. In this study, we examined the effects of NG-acylated imidazolylpropylguanidines substituted with a single phenyl or cyclohexyl substituent on H1R and H2R species isoforms expressed in Sf9 insect cells. N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57) turned out to be the most potent hH2R agonist identified so far (EC50 of 23 nM in the GTPase assay at the hH2R-Gsα fusion protein expressed in Sf9 insect cells). UR-AK57 was almost a full-hH2R agonist and only slightly less potent and efficacious than at gpH2R-Gsα. Several NG-acylated imidazolylpropylguanidines showed similar potency at hH2R and gpH2R. Most unexpectedly, UR-AK57 exhibited moderately strong partial hH1R agonism with a potency similar to that of histamine, whereas at gpH1R, UR-AK57 was only a very weak partial agonist. Structure/activity relationship studies revealed that both the alkanoyl chain connecting the aromatic or alicyclic substituent with the guanidine moiety and the nature of the carbocycle (cyclohexyl versus phenyl ring) critically determine the pharmacological properties of this class of compounds. Collectively, our data show that gpH1R and gpH R do not necessarily exhibit preference for bulky agonists 2compared with hH1R and hH2R, respectively, and that UR-AK57 is a promising starting point for the development of both potent and efficacious hH1R and hH2R agonists.
Footnotes
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This work was supported by the National Institutes of Health COBRE Award 1 P20 RR15563 and matching support from the State of Kansas and the University of Kansas (to R.S. and Q.-Z.Y.) and the Graduate Training Program (Graduiertenkolleg GRK 760, “Medicinal Chemistry: Molecular Recognition—Ligand-Receptor Interactions”) of the Deutsche Forschungsgemeinschaft (to R.S., S.E., and A.B.).
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doi:10.1124/jpet.106.102897.
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ABBREVIATIONS: HIS, histamine; UR-AK57, N1-(3-cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine; AIPG, NG-acylated imidazolylpropylguanidine; GPCR, G-protein-coupled receptor; gpH1R, guinea pig histamine H1-receptor; gpH2R, guinea pig histamine H2-receptor; gpH2R-GsαS, fusion protein of the guinea pig histamine H2-receptor and the short splice variant of Gsα;hH1R, human histamine H1-receptor; hH2R, human histamine H2-receptor; hH2R-GsαS, fusion protein of the human histamine H2-receptor and the short splice variant of Gsα; HIS, histamine; RGS, regulator of G-protein signaling; TM, transmembrane domain.
- Received February 13, 2006.
- Accepted March 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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