Solution conformation of c‐[Gln‐Trp‐Phe‐Gly‐Leu‐Met], a NK‐2 tachykinin antagonist

Amodeo, Pietro; Rovero, Paolo; Saviano, Gabriella; Temussi, Piero Andrea

doi:10.1111/j.1399-3011.1994.tb01144.x

International Journal of Peptide and Protein Research

1994

DOI: 10.1111/j.1399-3011.1994.tb01144.x

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Solution conformation of c‐[Gln‐Trp‐Phe‐Gly‐Leu‐Met], a NK‐2 tachykinin antagonist

Pietro Amodeo

Paolo Rovero²,

Gabriella Saviano

et al.

Abstract: The conformation of cyclo-[ Gln-Trp-Phe-Gly-Leu-Met], a potent tachykinin antagonist selective for the NK-2 receptor, has been studied by 'H NMR spectroscopy in DMSO-d6 and in a DMSO-d6/H20 cryoprotective mixture in the temperature range 280-320 K. The NMR data cannot be interpreted on the basis of a single ordered conformation. An exhaustive search, based mainly on missing NOES among skeleton protons, yields a description of the conformational state in solution consisting of a few interconverting structures t… Show more

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Cited by 4 publications

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Tailoring the nuclear Overhauser effect for the study of small and medium-sized molecules by solvent viscosity manipulation

Lameiras

2021

Progress in Nuclear Magnetic Resonance Spectroscopy

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The nuclear Overhauser effect (NOE) is a consequence of cross-relaxation between nuclear spins mediated by dipolar coupling. Its sensitivity to internuclear distances has made it an increasingly important tool for the determination of throughspace atom proximity relationships within molecules of sizes ranging from the smallest systems to large biopolymers. With the support of sophisticated FT-NMR techniques, the NOE plays an essential role in structure elucidation, conformational and dynamic investigations in liquid-state NMR. The efficiency of magnetization transfer by the NOE depends on the molecular rotational correlation time, whose value depends on solution viscosity. The magnitude of the NOE between 1 H nuclei varies from +50 % when molecular tumbling is fast to -100% when it is slow, the latter case corresponding to the spin diffusion limit.In an intermediate tumbling regime, the NOE may be vanishingly small. Increasing the viscosity of the solution increases the motional correlation time, and as a result, otherwise unobservable NOEs may be revealed and brought close to the spin diffusion limit. The goal of this review is to report the resolution of structural problems that benefited from the manipulation of the negative NOE by means of viscous solvents, including examples of molecular structure determination, conformation elucidation and mixture analysis (the ViscY method).3.7. Overview of advantages/disadvantages of viscous solvents in molecule mixture analysis 68 Conclusion 71Acknowledgements References 71Glossary 82

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Tailoring the nuclear Overhauser effect for the study of small and medium-sized molecules by solvent viscosity manipulation

Lameiras

2021

Progress in Nuclear Magnetic Resonance Spectroscopy

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A novel super-potent neurokinin A receptor antagonist containing dehydroalanine

Lombardi¹,

D’Agostino²,

Nastri³

et al. 1998

Bioorganic & Medicinal Chemistry Letters

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A Novel Rigid β-Turn Molecular Scaffold

et al. 1998

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We describe here the solution 1H NMR analysis, restrained and unrestrained molecular dynamic simulations of the bicyclic peptide cyclo(Met1-asp2-Trp3-Phe4-dap5-Leu6)cyclo(2β-5β) (MEN10701) (dap: (2R)-2,3-diaminopropionic acid). This compound is an analogue of cyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)cyclo(2β-5β) (MEN10627) (Dap: (2S)-2,3-diaminopropionic acid), which is the most potent and selective, peptide-based NK2 receptor antagonist known to date. MEN10701 differs from MEN10627 for the d chirality of the Asp2 and Dap5 residues; it was designed to better understand the role of the lactame bridge in determining the shape of the molecule and to elucidate whether its position, above or below the plane containing the pharmacophores (Met1, Trp3, Phe4, and Leu6 side chains), could modulate the biological response. Despite our expectations, the uncoercible bicyclic structure of MEN10627 is dramatically coerced into a novel conformation, by the replacement of the lactame bridge forming units (Asp2 and Dap5) with residues of opposite chirality. The overall shape of MEN10701 is also quite unique because of its compactness. It is ellipsoidal instead of being rectangle-like, and the structure is stabilized by two intramolecular hydrogen bonds encompassing two type I‘ β-turns. This structure can be added to the repertoire of rigid β-turn scaffolds for the design of bioactive molecules, which require turned motifs to elicit potency and specificity.

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Solution conformation of c‐[Gln‐Trp‐Phe‐Gly‐Leu‐Met], a NK‐2 tachykinin antagonist

Cited by 4 publications

References 16 publications

Tailoring the nuclear Overhauser effect for the study of small and medium-sized molecules by solvent viscosity manipulation

Tailoring the nuclear Overhauser effect for the study of small and medium-sized molecules by solvent viscosity manipulation

A novel super-potent neurokinin A receptor antagonist containing dehydroalanine

A Novel Rigid β-Turn Molecular Scaffold

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