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

Scarry, Sarah M.; Lovell, Kimberly M.; Frankowski, Kevin J.; Bohn, Laura M.; Aubé, Jeffrey

doi:10.1021/acs.joc.6b01350

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…Several KOR-selective pharmacophores have been recently reported and characterized ( Frankowski et al, 2010 , 2012 ; Nagase et al, 2010 ; Spetea et al, 2012 ; Bourgeois et al, 2014 ; Hirayama et al, 2014 ; Riley et al, 2014 ; Scarry et al, 2016 ). The current study follows from a report ( Spetea et al, 2012 ) of novel compounds based on a diphenethylamine structural backbone known to interact with the dopamine D2 receptor and reported to also have KOR antagonist activity in in vitro rodent tissue binding assays and bioassays ( Fortin et al, 1991 ).…”

Section: Introductionmentioning

confidence: 99%

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Dunn

Reed

Guariglia

et al. 2018

International Journal of Neuropsychopharmacology

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BackgroundThe kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).MethodsBPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.ResultsBPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.ConclusionsBPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

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Section: Introductionmentioning

confidence: 99%

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Dunn

Reed

Guariglia

et al. 2018

International Journal of Neuropsychopharmacology

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“…The chemical mechanism of the spontaneous aerobic oxidation is currently unknown, although similar oxidations to form heterocycles have been documented. − The reaction could possibly proceed via a radical pathway involving a captodative radical at the C-3 position of the pyrazinone . In such a case, a C-3 cyclopropyl group might be expected to undergo ring opening. , However, upon submission to the standard conditions, pyrazinone 1j , which contains a cyclopropyl group at this position, was obtained, albeit in a slightly lower yield (33%), but without any observable byproduct resulting from ring opening.…”

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confidence: 99%

Synthesis of the Nonribosomal Peptide Phevalin and Analogs

et al. 2019

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Phevalin, a cyclic nonribosomal peptide produced by Staphylococcus aureus, has intriguing biological properties. A synthetic route to access phevalin and similar pyrazinone natural products tyrvalin, leuvalin, phileucin, and a few synthetic analogs is described. The reaction sequence involves a one-pot carbamate deprotection/ imine formation/aerobic oxidation to form the pyrazinone-containing products.

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“…Moreover, we always observed, by LC/MS and 1 H NMR spectroscopy, the occurrence of a sizable amount of the aromatized derivative 32, which is in accordance with related results described in a later publication. 10 Along with these two compounds, we also noticed the occurrence of the aminoisoquinoline 30, plausibly resulting from a high temperature DMSO-based reduction process. 11 Eventually, we employed a different set of reported conditions 12 involving copper oxide instead of copper chloride, a somewhat larger excess of the amino acid, a much lower reaction temperature of 90 °C, and an extended reaction time of 40 hours.…”

Section: Paper Synthesismentioning

confidence: 80%

On Pyridopyrazinol Chemistry: Synthesis of Chemiluminescent Substances

et al. 2021

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Our work on new chemiluminescent substances related to the marine luciferin coelenterazine (λmax = 465 nm) led us to attempt the synthesis of four nitrogen-rich pyridopyrazine-bearing analogues. Accordingly, we studied the preparation of the corresponding benzyl-bearing pyridopyrazinols. By varying the conditions of condensations of phenylpyruvic acid and 1,2-diaminopyrine or 3,4-diaminopyridine, all the possible pyridopyrazin-2-ol regioisomers were isolated and properly characterized including by means of crystallographic studies. The ensuing synthesis of the halogenated pyridopyrazines was fraught with difficulties ranging from extensive decomposition to an unexpected ring contraction. In one instance, the inherently reductive mixture of phosphorus oxychloride and phosphorus trichloride provided the 2-benzyl-3-chloropyrido[2,3-b]pyrazine. This precursor was then transformed into the target O-acetylated luciferin (6,8-dibenzylimidazo[1,2-a]pyrido[3,2-e]pyrazin-9-yl acetate). The “benzo” derivative of this analogue (e.g.: 2,12-dibenzylimidazo[1',2':1,6]pyrazino[2,3-c]isoquinolin-3-yl acetate) was also made and the chemiluminescence emission spectra of these compounds were determined in a phosphate buffer (λmax = 546 and 462 nm).

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

Cited by 8 publications

References 27 publications

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice

Synthesis of the Nonribosomal Peptide Phevalin and Analogs

On Pyridopyrazinol Chemistry: Synthesis of Chemiluminescent Substances

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