New high affinity H3 receptor agonists without a basic side chain

Ruengwit Kitbunnadaj; Marcel Hoffmann; Silvina A. Fratantoni; Gerold Bongers; Remko A. Bakker; Kerstin Wieland; Ahmed El Jilali; Iwan J.P. De Esch; Wiro M.P.B. Menge; Henk Timmerman; Rob Leurs

doi:10.1016/j.bmc.2005.09.002

New high affinity H₃ receptor agonists without a basic side chain

Ruengwit Kitbunnadaj, Marcel Hoffmann, Silvina A. Fratantoni, Gerold Bongers, Remko A. Bakker, Kerstin Wieland, Ahmed El Jilali, Iwan J.P. De Esch, Wiro M.P.B. Menge, Henk Timmerman, Rob Leurs

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

In this study, we replaced the basic amine function of the known histamine H₃ receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H₃ receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H₃ receptor over the human H₄ receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H₃ receptor agonist (pK_i = 8.0 and pEC₅₀ = 8.1) with a 320-fold selectivity at the human H₃ receptor over the human H ₄ receptor.

Original language	English
Pages (from-to)	6309-6323
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	23
DOIs	https://doi.org/10.1016/j.bmc.2005.09.002
State	Published - 1 Dec 2005
Externally published	Yes

Keywords

Agonists
Histamine H receptor
Selective

Access to Document

10.1016/j.bmc.2005.09.002

Cite this

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title = "New high affinity H3 receptor agonists without a basic side chain",

abstract = "In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.",

keywords = "Agonists, Histamine H receptor, Selective",

author = "Ruengwit Kitbunnadaj and Marcel Hoffmann and Fratantoni, {Silvina A.} and Gerold Bongers and Bakker, {Remko A.} and Kerstin Wieland and {El Jilali}, Ahmed and {De Esch}, {Iwan J.P.} and Menge, {Wiro M.P.B.} and Henk Timmerman and Rob Leurs",

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doi = "10.1016/j.bmc.2005.09.002",

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AU - Kitbunnadaj, Ruengwit

AU - Hoffmann, Marcel

AU - Fratantoni, Silvina A.

AU - Bongers, Gerold

AU - Bakker, Remko A.

AU - Wieland, Kerstin

AU - El Jilali, Ahmed

AU - De Esch, Iwan J.P.

AU - Menge, Wiro M.P.B.

AU - Timmerman, Henk

AU - Leurs, Rob

PY - 2005/12/1

Y1 - 2005/12/1

N2 - In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.

AB - In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.

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