N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl) propyl]guanidine (UR-AK57), a potent partial agonist for the human histamine H1- and H2- receptors

Sheng Xue Xie, Anja Kraus, Prasanta Ghorai, Qizhuang Ye, Sigurd Elz, Armin Buschauer, Roland Seifert

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Both the histamine H1-receptor (H1R) and H 2-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-Cyclohexyl-butanoyl)-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-G fusion protein expressed in Sf9 insect cells). UR-AK57 was almost a full-hH2R agonist and only slightly less potent and efficacious than at gpH 2R-G. 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 gpH2R do not necessarily exhibit preference for bulky agonists compared 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.

Original languageEnglish (US)
Pages (from-to)1262-1268
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number3
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Histamine H1 Receptors
Histamine H2 Receptors
Sf9 Cells
Insects
Protein Isoforms
Pharmacology
GTP Phosphohydrolases
Guanidine
Structure-Activity Relationship
Histamine
Guinea Pigs
N1-(3-cyclohexylbutanoyl)-N2-(3-(1H-imidazol-4-yl)propyl)guanidine
Proteins

ASJC Scopus subject areas

  • Pharmacology

Cite this

N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl) propyl]guanidine (UR-AK57), a potent partial agonist for the human histamine H1- and H2- receptors. / Xie, Sheng Xue; Kraus, Anja; Ghorai, Prasanta; Ye, Qizhuang; Elz, Sigurd; Buschauer, Armin; Seifert, Roland.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 3, 06.2006, p. 1262-1268.

Research output: Contribution to journalArticle

Xie, Sheng Xue ; Kraus, Anja ; Ghorai, Prasanta ; Ye, Qizhuang ; Elz, Sigurd ; Buschauer, Armin ; Seifert, Roland. / N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl) propyl]guanidine (UR-AK57), a potent partial agonist for the human histamine H1- and H2- receptors. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 3. pp. 1262-1268.
@article{76652353fcff4f5fbd2b5650924192f2,
title = "N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl) propyl]guanidine (UR-AK57), a potent partial agonist for the human histamine H1- and H2- receptors",
abstract = "Both the histamine H1-receptor (H1R) and H 2-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-Cyclohexyl-butanoyl)-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 gpH 2R-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 gpH2R do not necessarily exhibit preference for bulky agonists compared 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.",
author = "Xie, {Sheng Xue} and Anja Kraus and Prasanta Ghorai and Qizhuang Ye and Sigurd Elz and Armin Buschauer and Roland Seifert",
year = "2006",
month = "6",
doi = "10.1124/jpet.106.102897",
language = "English (US)",
volume = "317",
pages = "1262--1268",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl) propyl]guanidine (UR-AK57), a potent partial agonist for the human histamine H1- and H2- receptors

AU - Xie, Sheng Xue

AU - Kraus, Anja

AU - Ghorai, Prasanta

AU - Ye, Qizhuang

AU - Elz, Sigurd

AU - Buschauer, Armin

AU - Seifert, Roland

PY - 2006/6

Y1 - 2006/6

N2 - Both the histamine H1-receptor (H1R) and H 2-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-Cyclohexyl-butanoyl)-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 gpH 2R-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 gpH2R do not necessarily exhibit preference for bulky agonists compared 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.

AB - Both the histamine H1-receptor (H1R) and H 2-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-Cyclohexyl-butanoyl)-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 gpH 2R-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 gpH2R do not necessarily exhibit preference for bulky agonists compared 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.

UR - http://www.scopus.com/inward/record.url?scp=33646762497&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646762497&partnerID=8YFLogxK

U2 - 10.1124/jpet.106.102897

DO - 10.1124/jpet.106.102897

M3 - Article

C2 - 16554355

AN - SCOPUS:33646762497

VL - 317

SP - 1262

EP - 1268

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -