Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties

Huang, Guozheng; Nimczick, Martin; Decker, Michael

doi:10.1002/ardp.201500079

Cited by 7 publications

(4 citation statements)

References 100 publications

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“…This idea dates back to Porthogese’s message-address concept that was applied to the development of opioid receptor dimer antagonists . All bivalent ligands can be further categorized as homo- or heterobivalent, depending on whether the same pharmacophore is engaging both binding sites or not. − …”

Section: Bitopic Ligandsmentioning

confidence: 99%

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

2017

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G protein-coupled receptors (GPCRs) belong to a large superfamily of membrane receptors mediating a variety of physiological functions. As such they are attractive targets for drug therapy. However, it remains a challenge to develop subtype selective GPCR ligands due to the high conservation of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding sites. Computational studies on ligand binding to GPCRs have revealed transient, low-affinity binding sites, termed metastable binding sites. Metastable binding sites may provide a new source of allosteric binding sites that could be exploited in the design of bitopic ligands. Unlike the bitopic ligands that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites.

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Section: Bitopic Ligandsmentioning

confidence: 99%

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

2017

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“…To this end, dualsteric modulators [36][37][38][39][40][41][42][43][44][45] have entered the scientific field. Just like its name, it has two pharmacophores, each binding at the orthosteric and the allosteric site.…”

Section: Chengwei Wumentioning

confidence: 99%

Designing drugs and chemical probes with the dualsteric approach

Zha,

He,

et al. 2023

Chem. Soc. Rev.

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“…1–2 Efforts have been made to synthesize opioids that interact either singly or via orthosteric 13 and allosteric mechanisms. 14 Bivalent ligands 15 have been synthesized that interact with μ- and κ-ORs 14 that may exist as receptor dimers. 16 Many non-selective opioids interact with two or all three of the main types of ORs by any, or several, of these routes.…”

Section: Introductionmentioning

confidence: 99%

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

Truong

Hassan

Lee

et al. 2017

Bioorganic & Medicinal Chemistry

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The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3 to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(−) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(−)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the μ,-opioid receptor (e.g., 1R,5R,9S-16: Ki = 0.073, 0.74, and 1.99 nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy μ-agonists (EC50 = 0.74 and 18.5 nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S, 5S,9R-16 was unusual, it had good affinity for the μ-OR (Ki = 26.5 nM) and was an efficacious μ-antagonist (Ke = 29.1 nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16 μ-agonist and the previously synthesized (1R,5R,9S)-(−)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(−)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.

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Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties

Cited by 7 publications

References 100 publications

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

Bitopic Ligands and Metastable Binding Sites: Opportunities for G Protein-Coupled Receptor (GPCR) Medicinal Chemistry

Designing drugs and chemical probes with the dualsteric approach

Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study

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