Importance of the aromatic residue at position 6 of [Nle10]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation

Dmitry S. Gembitsky, Mark Murnin, Ferenc L. Ötvös, James Allen, Richard F. Murphy, Sándor Lovas

Research output: Contribution to journalArticle

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Abstract

Steric and electrostatic requirements at position 6 of [Nle10]NKA(4- 10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe6,Nle10]NKA(4-10), where X = F, Cl, Br, I, NH2, NO2, and (b) [D-Phe6,Nle10]NKA(4-10), [Trp6,Nle10]NKA(4-10), and [Chex- Ala6,Nle10]NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle10]NKA(4-10) ≃ [p-F-Phe6,Nle10]NKA(4-10) > [p-NH2- Phe6,Nle10]NKA(4-10) > [p-Cl-Phe6,Nle10]NKA(4-10) > [p-NO2- Phe6,Nle10]NKA(4-10) > [Trp6,Nle10]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electrondonating and electron-withdrawing properties of the para- substituent were less important. The results favor the hypothesis that weakly polar π-π interactions exist between the aromatic group and the receptor.

Original languageEnglish
Pages (from-to)3004-3007
Number of pages4
JournalJournal of Medicinal Chemistry
Volume42
Issue number15
DOIs
StatePublished - Jul 29 1999

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Neurokinin-2 Receptors
Chemical activation
Bioactivity
neurokinin A(4-10)
Molecular recognition
CHO Cells
Static Electricity
Cricetinae
Electrostatics

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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Importance of the aromatic residue at position 6 of [Nle10]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation. / Gembitsky, Dmitry S.; Murnin, Mark; Ötvös, Ferenc L.; Allen, James; Murphy, Richard F.; Lovas, Sándor.

In: Journal of Medicinal Chemistry, Vol. 42, No. 15, 29.07.1999, p. 3004-3007.

Research output: Contribution to journalArticle

Gembitsky, Dmitry S. ; Murnin, Mark ; Ötvös, Ferenc L. ; Allen, James ; Murphy, Richard F. ; Lovas, Sándor. / Importance of the aromatic residue at position 6 of [Nle10]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 15. pp. 3004-3007.
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abstract = "Steric and electrostatic requirements at position 6 of [Nle10]NKA(4- 10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe6,Nle10]NKA(4-10), where X = F, Cl, Br, I, NH2, NO2, and (b) [D-Phe6,Nle10]NKA(4-10), [Trp6,Nle10]NKA(4-10), and [Chex- Ala6,Nle10]NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle10]NKA(4-10) ≃ [p-F-Phe6,Nle10]NKA(4-10) > [p-NH2- Phe6,Nle10]NKA(4-10) > [p-Cl-Phe6,Nle10]NKA(4-10) > [p-NO2- Phe6,Nle10]NKA(4-10) > [Trp6,Nle10]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electrondonating and electron-withdrawing properties of the para- substituent were less important. The results favor the hypothesis that weakly polar π-π interactions exist between the aromatic group and the receptor.",
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AU - Ötvös, Ferenc L.

AU - Allen, James

AU - Murphy, Richard F.

AU - Lovas, Sándor

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AB - Steric and electrostatic requirements at position 6 of [Nle10]NKA(4- 10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe6,Nle10]NKA(4-10), where X = F, Cl, Br, I, NH2, NO2, and (b) [D-Phe6,Nle10]NKA(4-10), [Trp6,Nle10]NKA(4-10), and [Chex- Ala6,Nle10]NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle10]NKA(4-10) ≃ [p-F-Phe6,Nle10]NKA(4-10) > [p-NH2- Phe6,Nle10]NKA(4-10) > [p-Cl-Phe6,Nle10]NKA(4-10) > [p-NO2- Phe6,Nle10]NKA(4-10) > [Trp6,Nle10]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electrondonating and electron-withdrawing properties of the para- substituent were less important. The results favor the hypothesis that weakly polar π-π interactions exist between the aromatic group and the receptor.

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