Abstract
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Analgesics, Opioid / chemical synthesis
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Analgesics, Opioid / chemistry
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Analgesics, Opioid / pharmacology*
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Animals
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Dose-Response Relationship, Drug
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Humans
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Mice
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Molecular Structure
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Narcotic Antagonists / chemical synthesis
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Narcotic Antagonists / chemistry
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Narcotic Antagonists / pharmacology*
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Pain / drug therapy*
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Receptors, Opioid, mu / agonists*
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Receptors, sigma / antagonists & inhibitors*
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Sigma-1 Receptor
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Structure-Activity Relationship
Substances
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Amides
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Analgesics, Opioid
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Narcotic Antagonists
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Receptors, Opioid, mu
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Receptors, sigma
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propionamide