bis-Pyridinium cyclophanes: Novel ligands with high affinity for the blood-brain barrier choline transporter

Zhenfa Zhang; Paul R. Lockman; Rajendar K. Mittapalli; David D. Allen; Linda P. Dwoskin; Peter A. Crooks

doi:10.1016/j.bmcl.2008.08.099

bis-Pyridinium cyclophanes: Novel ligands with high affinity for the blood-brain barrier choline transporter

Zhenfa Zhang, Paul R. Lockman, Rajendar K. Mittapalli, David D. Allen, Linda P. Dwoskin, Peter A. Crooks

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

12 Scopus citations

Abstract

A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N′-(1,10-decanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N′-(1,9-nonanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with K_i values of 0.8 μM and 1.4 μM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.

Original language	English
Pages (from-to)	5622-5625
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2008.08.099
State	Published - Oct 15 2008

Bibliographical note

Funding Information:
This work was supported by National Institute of Health Grant U19 DA017548.

Funding

This work was supported by National Institute of Health Grant U19 DA017548.

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Drug Abuse	U19DA017548

Keywords

Blood-brain barrier choline transporter
Nicotinic acetylcholine receptor
Quaternary ammonium

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2008.08.099

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title = "bis-Pyridinium cyclophanes: Novel ligands with high affinity for the blood-brain barrier choline transporter",

abstract = "A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N′-(1,10-decanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N′-(1,9-nonanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with Ki values of 0.8 μM and 1.4 μM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.",

keywords = "Blood-brain barrier choline transporter, Nicotinic acetylcholine receptor, Quaternary ammonium",

author = "Zhenfa Zhang and Lockman, {Paul R.} and Mittapalli, {Rajendar K.} and Allen, {David D.} and Dwoskin, {Linda P.} and Crooks, {Peter A.}",

note = "Funding Information: This work was supported by National Institute of Health Grant U19 DA017548.",

year = "2008",

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doi = "10.1016/j.bmcl.2008.08.099",

language = "English",

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T2 - Novel ligands with high affinity for the blood-brain barrier choline transporter

AU - Zhang, Zhenfa

AU - Lockman, Paul R.

AU - Mittapalli, Rajendar K.

AU - Allen, David D.

AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

N1 - Funding Information: This work was supported by National Institute of Health Grant U19 DA017548.

PY - 2008/10/15

Y1 - 2008/10/15

N2 - A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N′-(1,10-decanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N′-(1,9-nonanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with Ki values of 0.8 μM and 1.4 μM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.

AB - A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N′-(1,10-decanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N′-(1,9-nonanediyl)3,3′-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with Ki values of 0.8 μM and 1.4 μM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.

KW - Blood-brain barrier choline transporter

KW - Nicotinic acetylcholine receptor

KW - Quaternary ammonium

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JO - Bioorganic and Medicinal Chemistry Letters

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bis-Pyridinium cyclophanes: Novel ligands with high affinity for the blood-brain barrier choline transporter

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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