Discovery of Potent Cyclic Pseudopeptide Human Tachykinin NK-2 Receptor Antagonists

Giannotti, Danilo; Perrotta, Enzo; Bugno, Cristina Di; Nannicini, Rossano; Harmat, Nicholas J. S.; Giolitti, Alessandro; Patacchini, Riccardo; Renzetti, Anna Rita; Rotondaro, Luigi; Giuliani, Sandro; Altamura, Maria Maddalena; Maggi, Carlo Alberto

doi:10.1021/jm0010217

Cited by 16 publications

(19 citation statements)

References 15 publications

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“…Gln166Ala. This mutation was previously reported not to affect the binding of nepadutant; on the other hand, the affinity of MEN11558 is decreased 5-fold.…”

Section: Resultsmentioning

confidence: 60%

“…The conformational equivalence of the common subset was confirmed . An additional benzyl group was then introduced in different positions of 5a .…”

Section: Monocyclic Antagonistsmentioning

confidence: 82%

“…In the preliminary work, we took a step back from the bicyclic structure of MEN10627, the precursor of nepadutant, to identify the smallest structural subset retaining micromolar affinity for the human NK-2 receptor. This is represented in Figure .…”

Section: Monocyclic Antagonistsmentioning

confidence: 99%

“…This is represented in Figure .

3 Smallest structural subset in MEN10627 retaining micromolar affinity (from ref ). …”

Section: Monocyclic Antagonistsmentioning

confidence: 99%

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Monocyclic Human Tachykinin NK-2 Receptor Antagonists as Evolution of a Potent Bicyclic Antagonist: QSAR and Site-Directed Mutagenesis Studies

et al. 2002

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A new series of monocyclic pseudopeptidic tachykinin NK-2 receptor antagonists has been derived from nepadutant with the help of site-directed mutagenesis studies and QSAR models. MEN11558 is the lead compound which is evaluated on a series of 13 new human tachykinin NK-2 receptor mutants (Tyr107Ala, Gln109Ala, Asn110Ala, Phe112Ala, Ser164Phe, Cys167Gly, Phe168Ala, Tyr169Ala, Ile202Phe, Trp263Ala, Tyr269Phe, Tyr269Ala, and Phe293Ala) and 8 mutants on which data from nepadutant were already available (Gln166Ala, Ser170Ala, Thr171Ala, His198Ala, Tyr206Phe, Tyr266Phe, Tyr289Phe, and Tyr289Thr). The results show that the two compounds share most of their binding sites, in agreement with their hypothesized binding modes. This allows us to transfer the structural knowledge we already had for nepadutant to the new series of compounds. At the same time, a sound QSAR model is developed to assist the prioritization of new chemical syntheses. The result is the discovery of receptor antagonists with a higher affinity than nepadutant for the hNK-2 receptor.

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“…Gln166Ala. This mutation was previously reported not to affect the binding of nepadutant; on the other hand, the affinity of MEN11558 is decreased 5-fold.…”

Section: Resultsmentioning

confidence: 60%

“…The conformational equivalence of the common subset was confirmed . An additional benzyl group was then introduced in different positions of 5a .…”

Section: Monocyclic Antagonistsmentioning

confidence: 82%

Section: Monocyclic Antagonistsmentioning

confidence: 99%

“…This is represented in Figure .

3 Smallest structural subset in MEN10627 retaining micromolar affinity (from ref ). …”

Section: Monocyclic Antagonistsmentioning

confidence: 99%

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Monocyclic Human Tachykinin NK-2 Receptor Antagonists as Evolution of a Potent Bicyclic Antagonist: QSAR and Site-Directed Mutagenesis Studies

et al. 2002

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“…Its very low bioavailability, however, prevents it from being used as a drug. We have already shown (Giannotti et al, 2000;Giolitti et al, 2002) the design rationale for reducing its size and complexity, selecting part of the structure retaining the -turn feature of one of the cycles, which we considered responsible for the ability to effectively bind the hNK-2 receptor. Two series of hNK-2 antagonists originated deriving from theoretical assumptions with the support of modelling: a monocyclic one (Fedi et al, 2004) and a further simplified linear one (Sisto et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

New monocyclic and acyclic hNK-2 antagonists retaining the β-turn feature. X-ray and molecular modelling studies

Altamura

Dapporto

Fedi

et al. 2006

Acta Crystallogr Sect B

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The human tachykinin NK-2 (hNK-2) receptor is considered a promising target for relevant pathologies at the respiratory, gastrointestinal and genitourinary level. With the aim of reducing the complexity of existing peptide antagonists, two series of hNK-2 receptor antagonists were designed, with the support of modelling, and synthesized. The X-ray structure determination of two compounds, each belonging to one of the two series, allowed the experimental validation of the initial rationale. In addition, it has been found that the two series share a -turn structure, a key feature for binding the hNK-2 receptor.

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Aspects of Peptidomimetics

Maes¹,

Tourwé²

2009

Peptide and Protein Design for Biopharmaceutical Applications

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Discovery of Potent Cyclic Pseudopeptide Human Tachykinin NK-2 Receptor Antagonists

Cited by 16 publications

References 15 publications

Monocyclic Human Tachykinin NK-2 Receptor Antagonists as Evolution of a Potent Bicyclic Antagonist: QSAR and Site-Directed Mutagenesis Studies

Monocyclic Human Tachykinin NK-2 Receptor Antagonists as Evolution of a Potent Bicyclic Antagonist: QSAR and Site-Directed Mutagenesis Studies

New monocyclic and acyclic hNK-2 antagonists retaining the β-turn feature. X-ray and molecular modelling studies

Aspects of Peptidomimetics

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