Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies

Herman D. Lim; Enade P. Istyastono; Andrea van de Stolpe; Giuseppe Romeo; Silvia Gobbi; Marjo Schepers; Roger Lahaye; Wiro M.B.P. Menge; Obbe P. Zuiderveld; Aldo Jongejan; Rogier A. Smits; Remko A. Bakker; Eric E.J. Haaksma; Rob Leurs; Iwan J.P. de Esch

doi:https://doi.org/10.1016/j.bmc.2009.04.007

Clobenpropit analogs as dual activity ligands for the histamine H₃ and H₄ receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies

Herman D. Lim, Enade P. Istyastono, Andrea van de Stolpe, Giuseppe Romeo, Silvia Gobbi, Marjo Schepers, Roger Lahaye, Wiro M.B.P. Menge, Obbe P. Zuiderveld, Aldo Jongejan, Rogier A. Smits, Remko A. Bakker, Eric E.J. Haaksma, Rob Leurs, Iwan J.P. de Esch

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

34 Citations (Scopus)

Abstract

Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H₃ receptor (H₃R) and H₄ receptor (H₄R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H₃R and H₄R ligands. The compounds show moderate to high affinity for both the human H₃R and H₄R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H₄R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H₃R and H₄R affinities.

Original language	English
Pages (from-to)	3987-3994
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	11
DOIs	https://doi.org/10.1016/j.bmc.2009.04.007
Publication status	Published - 1 Jun 2009

Keywords

Clobenpropit analogs
Cross-target QSAR
GPCR
Histamine H receptor
Selectivity

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https://doi.org/10.1016/j.bmc.2009.04.007

Cite this

Lim, H. D., Istyastono, E. P., van de Stolpe, A., Romeo, G., Gobbi, S., Schepers, M., Lahaye, R., Menge, W. M. B. P., Zuiderveld, O. P., Jongejan, A., Smits, R. A., Bakker, R. A., Haaksma, E. E. J., Leurs, R., & de Esch, I. J. P. (2009). Clobenpropit analogs as dual activity ligands for the histamine H₃ and H₄ receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies. Bioorganic and Medicinal Chemistry, 17(11), 3987-3994. https://doi.org/10.1016/j.bmc.2009.04.007

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title = "Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies",

abstract = "Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H3 receptor (H3R) and H4 receptor (H4R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H3R and H4R ligands. The compounds show moderate to high affinity for both the human H3R and H4R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H4R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H3R and H4R affinities.",

keywords = "Clobenpropit analogs, Cross-target QSAR, GPCR, Histamine H receptor, Selectivity",

author = "Lim, {Herman D.} and Istyastono, {Enade P.} and {van de Stolpe}, Andrea and Giuseppe Romeo and Silvia Gobbi and Marjo Schepers and Roger Lahaye and Menge, {Wiro M.B.P.} and Zuiderveld, {Obbe P.} and Aldo Jongejan and Smits, {Rogier A.} and Bakker, {Remko A.} and Haaksma, {Eric E.J.} and Rob Leurs and {de Esch}, {Iwan J.P.}",

note = "Funding Information: We thank the Stichting voor de Technische Wetenschapppen of the Netherlands Foundation of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) for financial support through a PIONIER award to Rob Leurs. The histamine H 4 R research is supported by COST BM0806 (European Cooperation in Science and Technology). We thank Luc Roumen and Chris de Graaf for technical assistance and helpful discussions.",

year = "2009",

month = jun,

day = "1",

doi = "https://doi.org/10.1016/j.bmc.2009.04.007",

language = "English",

volume = "17",

pages = "3987--3994",

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Lim, HD, Istyastono, EP, van de Stolpe, A, Romeo, G, Gobbi, S, Schepers, M, Lahaye, R, Menge, WMBP, Zuiderveld, OP, Jongejan, A, Smits, RA, Bakker, RA, Haaksma, EEJ, Leurs, R & de Esch, IJP 2009, 'Clobenpropit analogs as dual activity ligands for the histamine H₃ and H₄ receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies', Bioorganic and Medicinal Chemistry, vol. 17, no. 11, pp. 3987-3994. https://doi.org/10.1016/j.bmc.2009.04.007

Clobenpropit analogs as dual activity ligands for the histamine H₃ and H₄ receptors: Synthesis, pharmacological evaluation, and cross-target QSAR studies. / Lim, Herman D.; Istyastono, Enade P.; van de Stolpe, Andrea et al.
In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 11, 01.06.2009, p. 3987-3994.

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

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T1 - Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors

T2 - Synthesis, pharmacological evaluation, and cross-target QSAR studies

AU - Lim, Herman D.

AU - Istyastono, Enade P.

AU - van de Stolpe, Andrea

AU - Romeo, Giuseppe

AU - Gobbi, Silvia

AU - Schepers, Marjo

AU - Lahaye, Roger

AU - Menge, Wiro M.B.P.

AU - Zuiderveld, Obbe P.

AU - Jongejan, Aldo

AU - Smits, Rogier A.

AU - Bakker, Remko A.

AU - Haaksma, Eric E.J.

AU - Leurs, Rob

AU - de Esch, Iwan J.P.

N1 - Funding Information: We thank the Stichting voor de Technische Wetenschapppen of the Netherlands Foundation of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) for financial support through a PIONIER award to Rob Leurs. The histamine H 4 R research is supported by COST BM0806 (European Cooperation in Science and Technology). We thank Luc Roumen and Chris de Graaf for technical assistance and helpful discussions.

PY - 2009/6/1

Y1 - 2009/6/1

N2 - Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H3 receptor (H3R) and H4 receptor (H4R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H3R and H4R ligands. The compounds show moderate to high affinity for both the human H3R and H4R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H4R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H3R and H4R affinities.

AB - Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H3 receptor (H3R) and H4 receptor (H4R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H3R and H4R ligands. The compounds show moderate to high affinity for both the human H3R and H4R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H4R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H3R and H4R affinities.

KW - Clobenpropit analogs

KW - Cross-target QSAR

KW - GPCR

KW - Histamine H receptor

KW - Selectivity

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DO - https://doi.org/10.1016/j.bmc.2009.04.007

M3 - Article

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EP - 3994

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