2018
DOI: 10.1021/acschemneuro.8b00349
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Structure–Activity Relationship Studies of 6α- and 6β-Indolylacetamidonaltrexamine Derivatives as Bitopic Mu Opioid Receptor Modulators and Elaboration of the “Message-Address Concept” To Comprehend Their Functional Conversion

Abstract: Structure-activity relationship (SAR) studies of numerous opioid ligands have shown that introduction of a methyl or ethyl group on the tertiary amino group at position 17 of the epoxymorphinan skeleton generally results in a mu opioid receptor (MOR) agonist while introduction of a cyclopropylmethyl group typically leads to an antagonist. Furthermore, it has been shown that introduction of heterocyclic ring systems at position 6 can favor antagonism. However, it was reported that 17-cyclopropylmethyl-3,14β-dih… Show more

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Cited by 32 publications
(120 citation statements)
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“…mitragynine pseudoindoxyl) and peptides (i.e. DAMGO) has been described 37,38,[41][42][43][44] . The interaction with Y148 is also recognized as an important requirement for ligands (small molecules and peptides) to bind to the µOR 37,38,[41][42][43][44] .…”
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confidence: 99%
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“…mitragynine pseudoindoxyl) and peptides (i.e. DAMGO) has been described 37,38,[41][42][43][44] . The interaction with Y148 is also recognized as an important requirement for ligands (small molecules and peptides) to bind to the µOR 37,38,[41][42][43][44] .…”
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confidence: 99%
“…DAMGO) has been described 37,38,[41][42][43][44] . The interaction with Y148 is also recognized as an important requirement for ligands (small molecules and peptides) to bind to the µOR 37,38,[41][42][43][44] . In this study, the oxygen of the partially saturated furan ring (E-ring) of the morphinan system serves as a hydrogen bond acceptor for Y148 in both series of N-methyl (1)(2)(3)(4) and N-phenethyl substituted morphinans (1a-4a).…”
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confidence: 99%
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“…Using these settings, we retrieved 15 virtual hits. The central role of Asp147 and Tyr148 of peptides, morphinans ligands, and other chemotypes for binding to the MOR is well recognized 22,[24][25][26][27][28][29][30][31][32][33][34] . Further, both of these interactions appeared to be critical for ligand binding in our previous study 26 .…”
Section: Resultsmentioning
confidence: 99%
“…In the search for ligands with new chemotypes and further understanding the mechanism by which known ligands (i.e. small molecules and peptides) bind and activate the MOR, structure-based discovery campaigns have used the high-resolution MOR structures to computationally investigate diverse molecules [25][26][27][28][29][30][31] . We have previously reported on a virtual screening campaign that led to the identification of novel chemotypes that displayed MOR antagonism in vitro and in vivo 26 .…”
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confidence: 99%