Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein

E.S. Edink, A. Akdemir, C.J.W. Jansen, R. van Elk, O.P. Zuiderveld, F.J.J. de Kanter, J.E. van Muijlwijk- Koezen, A.B. Smit, R. Leurs, I.J.P. de Esch

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes. © 2011 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)1448-1454
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number3
DOIs
Publication statusPublished - 2012

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Benzoates
Nicotinic Receptors
Structure-Activity Relationship
Acetylcholine
Carrier Proteins
Ligands
Computer Simulation
tropine
Proteins

Cite this

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title = "Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein",
abstract = "Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes. {\circledC} 2011 Elsevier Ltd. All rights reserved.",
author = "E.S. Edink and A. Akdemir and C.J.W. Jansen and {van Elk}, R. and O.P. Zuiderveld and {de Kanter}, F.J.J. and {van Muijlwijk- Koezen}, J.E. and A.B. Smit and R. Leurs and {de Esch}, I.J.P.",
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pages = "1448--1454",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
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Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein. / Edink, E.S.; Akdemir, A.; Jansen, C.J.W.; van Elk, R.; Zuiderveld, O.P.; de Kanter, F.J.J.; van Muijlwijk- Koezen, J.E.; Smit, A.B.; Leurs, R.; de Esch, I.J.P.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 3, 2012, p. 1448-1454.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein

AU - Edink, E.S.

AU - Akdemir, A.

AU - Jansen, C.J.W.

AU - van Elk, R.

AU - Zuiderveld, O.P.

AU - de Kanter, F.J.J.

AU - van Muijlwijk- Koezen, J.E.

AU - Smit, A.B.

AU - Leurs, R.

AU - de Esch, I.J.P.

PY - 2012

Y1 - 2012

N2 - Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes. © 2011 Elsevier Ltd. All rights reserved.

AB - Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype. The AChBP species differences are indicative of a difference in accessibility of a ligand-inducible subpocket. Hereby, we have identified a region that can be scrutinized to achieve selectivity for nicotinic receptor subtypes. © 2011 Elsevier Ltd. All rights reserved.

U2 - 10.1016/j.bmcl.2011.12.008

DO - 10.1016/j.bmcl.2011.12.008

M3 - Article

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EP - 1454

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

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