Design and synthesis of potential dual NK1/NK3 receptor antagonists

Hanessian, Stephen; Babonneau, Vincent; Boyer, Nicole; Cour, Clotilde Mannoury la; Millan, Mark J.; Nanteuil, Guillaume De

doi:10.1016/j.bmcl.2013.12.033

Cited by 9 publications

(12 citation statements)

References 32 publications

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“…This calculation predicts that while the receptor has an electronegative surface at the extracellular apex of the binding site, the ligands prefer to bind in a neutral deprotonated form due to solvent exposure of the ionizable sidechains and ligand functional groups. Our MM-PBSA calculations also predict that aprepitant is more potent than L760735, consistent with experiments (33). Hotspots for L760735 and aprepitant identified through MM/ GBSA free-energy decomposition (SI Appendix, Fig.…”

Section: Docking Of Antagonistssupporting

confidence: 85%

Crystal structure of the human NK ₁ tachykinin receptor

Yin

Chapman

Clark

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The NK1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1R (hNK1R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK1R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNK1R bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

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Section: Docking Of Antagonistssupporting

confidence: 85%

Crystal structure of the human NK ₁ tachykinin receptor

Yin

Chapman

Clark

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The exact distribution of this receptor in the brain is still unknown, but it seems to be found predominantly in cortical regions such as the frontal and parietal cortex, and also in the hippocampus [3][4][5] . Data from pre-clinical and clinical trials of non-peptide NK 3 antagonists used to treat schizophrenia have shown positive effects, with significant reduction of symptoms and lack of major side effects 3,[6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

et al. 2015

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Coarse-grained molecular dynamics simulations are used to calculate the free energies of transfer of miltefosine, an alkylphosphocholine anticancer agent, from water to lipid bilayers to study its mechanism of interaction with biological membranes. We consider bilayers containing lipids with different degrees of unsaturation: dipalmitoylphosphatidylcholine (DPPC, saturated, containing 0%, 10%, and 30% cholesterol), dioleoylphosphatidylcholine (DOPC, diunsaturated), palmitoyloleoylphosphatidylcholine (POPC, monounsaturated), diarachidonoylphosphatidylcholine (DAPC, polyunsaturated), and dilinoleylphosphatidylcholine (DUPC, polyunsaturated). These free energies, calculated using umbrella sampling, were used to compute the partition coefficients (K) of miltefosine between water and the lipid bilayers. The K values for the bilayers relative to that of pure DPPC were found to be 5.3 (DOPC), 7.0 (POPC), 1.0 (DAPC), 2.2 (DUPC), 14.9 (10% cholesterol), and 76.2 (30% cholesterol). Additionally, we calculated the free energy of formation of miltefosine-cholesterol complexes by pulling the surfactant laterally in the DPPC + 30% cholesterol system. The free energy profile that we obtained provides further evidence that miltefosine tends to associate with cholesterol and has a propensity to partition into lipid rafts. We also quantified the kinetics of the transport of miltefosine through the various bilayers by computing permeance values. The highest permeance was observed in DUPC bilayers (2.28 × 10(-2) m/s) and the lowest permeance in the DPPC bilayer with 30% cholesterol (1.10 × 10(-7) m/s). Our simulation results show that miltefosine does indeed interact with lipid rafts, has a higher permeability in polyunsaturated, loosely organized bilayers, and has higher flip-flop rates in specific regions of cellular membranes.

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“…Peptide 317 bound to a spiro‐linked heterocycle was synthesized using benzoxazinone 318 as one of component of the convergent scheme [299] . The obtained compound 317 showed activity as a new potent dual NK 1 /NK 3 (neurokinin 1 and neurokinin 3) antagonist with p K i values of 8.6 and 8.1, respectively [300] . Performance index of this compound in relation to neurokinin 3 is better than the similar data of the previously synthesized NK 3 R antagonist, compound 319 ( Figure 2).…”

Section: Some Biologically Active Compounds With a Spiro Carbon Centermentioning

confidence: 99%

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

Гатауллин

2020

Helvetica Chimica Acta

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The review covers the results of studies published in the literature on the synthesis of spiro-linked heterocycles of the indole, quinoline, benzoxazine, benzothiazine, indenoquinoxaline, pyridopyrimidine, and acridine series. Possible approaches to the synthesis of spirocycles through a sequence of well-known Knoevenagel, Michael reactions, deamination cyclization of 1,2-dicarbonyl, CH-acid compounds, direct cycloaddition of activated olefins to isatins, 3-alkylideneindoles, 2-oxindoles, in situ generated azomethine ylides, indenoquinoxalines are analyzed. Attention is drawn to approaches to the preparation of spiro-fused compounds using reactions of intra-and intermolecular dearomatization of indoles. Recent advances in the synthesis of spiro-linked benzo heterocycles from derivatives of 2-olefin substituted anilines are summarized. The examples of the synthesis of spiro-fused heterocycles by means of metal complexes catalyzed decomposition of diazo compounds are given. Some syntheses of biologically active representatives are shown, as well as the use of transformations of spiroheterocycles in the preparation of other heterocycles.

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Design and synthesis of potential dual NK1/NK3 receptor antagonists

Cited by 9 publications

References 32 publications

Crystal structure of the human NK ₁ tachykinin receptor

Crystal structure of the human NK ₁ tachykinin receptor

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

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Design and synthesis of potential dual NK1/NK3 receptor antagonists

Cited by 9 publications

References 32 publications

Crystal structure of the human NK 1 tachykinin receptor

Crystal structure of the human NK 1 tachykinin receptor

Understanding Miltefosine–Membrane Interactions Using Molecular Dynamics Simulations

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

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Product

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Crystal structure of the human NK ₁ tachykinin receptor

Crystal structure of the human NK ₁ tachykinin receptor