Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors

Clelia Dallanoce, Pietro Magrone, Carlo Matera, Fabio Frigerio, Giovanni Grazioso, Marco DeAmici, Sergio Fucile, Vanessa Piccari, Karla Frydenvang, Luca Pucci, Cecilia Gotti, Francesco Clementi, Carlo DeMicheli

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A set of racemic spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.

Original languageEnglish
Pages (from-to)889-903
Number of pages15
JournalChemMedChem
Volume6
Issue number5
DOIs
Publication statusPublished - May 2 2011

Fingerprint

Nicotinic Receptors
Quinuclidines
Enantiomers
Pharmacology
Derivatives
Rats
Cycloaddition Reaction
Cycloaddition
Ligands
Cell Line
Cells
Experiments
3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro(4.5)dec-2-ene
tartaric acid

Keywords

  • Δ-isoxazoline derivatives
  • α7 agonists
  • Electrophysiological assays
  • Neuronal nicotinic acetylcholine receptors
  • X-ray crystallography

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors. / Dallanoce, Clelia; Magrone, Pietro; Matera, Carlo; Frigerio, Fabio; Grazioso, Giovanni; DeAmici, Marco; Fucile, Sergio; Piccari, Vanessa; Frydenvang, Karla; Pucci, Luca; Gotti, Cecilia; Clementi, Francesco; DeMicheli, Carlo.

In: ChemMedChem, Vol. 6, No. 5, 02.05.2011, p. 889-903.

Research output: Contribution to journalArticle

Dallanoce, C, Magrone, P, Matera, C, Frigerio, F, Grazioso, G, DeAmici, M, Fucile, S, Piccari, V, Frydenvang, K, Pucci, L, Gotti, C, Clementi, F & DeMicheli, C 2011, 'Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors', ChemMedChem, vol. 6, no. 5, pp. 889-903. https://doi.org/10.1002/cmdc.201000514
Dallanoce, Clelia ; Magrone, Pietro ; Matera, Carlo ; Frigerio, Fabio ; Grazioso, Giovanni ; DeAmici, Marco ; Fucile, Sergio ; Piccari, Vanessa ; Frydenvang, Karla ; Pucci, Luca ; Gotti, Cecilia ; Clementi, Francesco ; DeMicheli, Carlo. / Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors. In: ChemMedChem. 2011 ; Vol. 6, No. 5. pp. 889-903.
@article{81be8e5f38d74b17b094dd3e945c5c02,
title = "Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors",
abstract = "A set of racemic spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.",
keywords = "Δ-isoxazoline derivatives, α7 agonists, Electrophysiological assays, Neuronal nicotinic acetylcholine receptors, X-ray crystallography",
author = "Clelia Dallanoce and Pietro Magrone and Carlo Matera and Fabio Frigerio and Giovanni Grazioso and Marco DeAmici and Sergio Fucile and Vanessa Piccari and Karla Frydenvang and Luca Pucci and Cecilia Gotti and Francesco Clementi and Carlo DeMicheli",
year = "2011",
month = "5",
day = "2",
doi = "10.1002/cmdc.201000514",
language = "English",
volume = "6",
pages = "889--903",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-Isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors

AU - Dallanoce, Clelia

AU - Magrone, Pietro

AU - Matera, Carlo

AU - Frigerio, Fabio

AU - Grazioso, Giovanni

AU - DeAmici, Marco

AU - Fucile, Sergio

AU - Piccari, Vanessa

AU - Frydenvang, Karla

AU - Pucci, Luca

AU - Gotti, Cecilia

AU - Clementi, Francesco

AU - DeMicheli, Carlo

PY - 2011/5/2

Y1 - 2011/5/2

N2 - A set of racemic spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.

AB - A set of racemic spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ2-Isoxazolines 3a (3-Br), 6a (3-OMe), 5a (3-Ph), 8a (3-OnPr), and 4a (3-Me) were the ligands with the highest affinity for the α7 subtype (Ki values equal to 13.5, 14.2, 25.0, 71.6, and 96.2nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6a was found to be the eutomer, with Ki values of 4.6 and 48.7nM against rat and human α7 receptors, respectively. Spirocyclic is better! Significant binding selectivity and functional activity toward α7 nAChR subtypes were achieved with new chiral derivatives, characterized by a Δ2-isoxazoline ring linked to a quinuclidine moiety with a spirocylic junction. The eutomer of the most promising derivative in the series, the 3-O-methoxy analogue (R)-(-)-6, fit well to a model for the α7 nAChRs.

KW - Δ-isoxazoline derivatives

KW - α7 agonists

KW - Electrophysiological assays

KW - Neuronal nicotinic acetylcholine receptors

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=79955005705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955005705&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201000514

DO - 10.1002/cmdc.201000514

M3 - Article

VL - 6

SP - 889

EP - 903

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 5

ER -