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Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-?]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence.

ABSTRACT: The quinoxaline and quinoxalinone family of nitrogen heterocycles is present in molecules of therapeutic relevance for diverse applications ranging from infectious diseases to neuroscience targets. Here, we describe a general synthetic sequence to afford pyrrolo[1,2-?]quinoxalinones from commercially available starting materials and their use in preparing potential kappa opioid receptor antagonists. The biological data obtained from the latter set of compounds is briefly presented and discussed.

SUBMITTER: Scarry SM

PROVIDER: S-EPMC5278949 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-α]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence.

Scarry Sarah M SM Lovell Kimberly M KM Frankowski Kevin J KJ Bohn Laura M LM Aubé Jeffrey J

The Journal of organic chemistry 20160802 21

The quinoxaline and quinoxalinone family of nitrogen heterocycles is present in molecules of therapeutic relevance for diverse applications ranging from infectious diseases to neuroscience targets. Here, we describe a general synthetic sequence to afford pyrrolo[1,2-α]quinoxalinones from commercially available starting materials and their use in preparing potential kappa opioid receptor antagonists. The biological data obtained from the latter set of compounds is briefly presented and discussed. ...[more]

PMID: 27399050

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Project description:Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.

Dataset Information

Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-?]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence.

Publications

Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-α]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence.

Similar Datasets

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