Abstract
A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.
MeSH terms
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Administration, Oral
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Animals
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Chemical Phenomena
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Chemistry, Physical
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Cycloparaffins / chemistry*
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Dogs
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / metabolism
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Hepatocytes / metabolism
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Humans
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Molecular Structure
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Narcotic Antagonists*
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Nociceptin Receptor
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Protein Binding
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Pyridines / administration & dosage*
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / classification
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Rats
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Receptors, Opioid / metabolism
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Structure-Activity Relationship
Substances
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Cycloparaffins
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Ether-A-Go-Go Potassium Channels
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Narcotic Antagonists
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Pyridines
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Receptors, Opioid
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Nociceptin Receptor