Abstract
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated.
Copyright (c) 2010. Published by Elsevier Ltd.
MeSH terms
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Animals
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Antidepressive Agents / chemical synthesis
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Antidepressive Agents / chemistry*
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Antidepressive Agents / pharmacokinetics
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Antidepressive Agents / pharmacology*
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Benzamides / chemical synthesis
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Benzamides / chemistry*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology*
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Brain / metabolism
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Bridged Bicyclo Compounds / chemical synthesis
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacokinetics
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Bridged Bicyclo Compounds / pharmacology
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Depressive Disorder, Major / drug therapy
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Humans
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Microsomes, Liver / metabolism
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Rats
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Receptors, Opioid, kappa / antagonists & inhibitors*
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Receptors, Opioid, kappa / metabolism*
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Structure-Activity Relationship
Substances
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Antidepressive Agents
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Benzamides
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Bridged Bicyclo Compounds
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Receptors, Opioid, kappa
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benzamide