Abstract
Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (K(i)>500 nM).
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Aza Compounds / chemistry*
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Heptanes / chemistry
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Humans
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Ligands
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Magnetic Resonance Spectroscopy
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Nicotinic Antagonists / chemical synthesis
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Nicotinic Antagonists / chemistry*
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Nicotinic Antagonists / metabolism
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Protein Binding
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Receptors, Nicotinic / chemistry*
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Receptors, Nicotinic / metabolism
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / metabolism
Substances
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Aza Compounds
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Heptanes
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Ligands
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Nicotinic Antagonists
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Protein Isoforms
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Receptors, Nicotinic
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Spiro Compounds
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nicotinic receptor alpha4beta2