Abstract
In looking for a novel achiral μ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent μ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Azabicyclo Compounds / chemical synthesis*
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Azabicyclo Compounds / chemistry*
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Azabicyclo Compounds / pharmacokinetics
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Azabicyclo Compounds / therapeutic use
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CHO Cells
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Cricetinae
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Cricetulus
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Dogs
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Drug Evaluation, Preclinical
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Hexanes / chemistry*
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Hexanes / pharmacokinetics
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Hexanes / therapeutic use
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Humans
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Ligands*
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Protein Binding
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Pruritus / drug therapy
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Rats
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Receptors, Opioid, mu / antagonists & inhibitors*
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Receptors, Opioid, mu / metabolism
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / therapeutic use
Substances
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Azabicyclo Compounds
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Hexanes
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Ligands
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Receptors, Opioid, mu
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Sulfonamides