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

doi:10.1021/jm9807151

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

Department of Biomedical Sciences

Research output: Contribution to journal › Article

12 Citations (Scopus)

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 language	English
Pages (from-to)	3004-3007
Number of pages	4
Journal	Journal of Medicinal Chemistry
Volume	42
Issue number	15
DOIs	https://doi.org/10.1021/jm9807151
State	Published - 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

Cite this

Gembitsky, D. S., Murnin, M., Ötvös, F. L., Allen, J., Murphy, R. F., & Lovas, S. (1999). Importance of the aromatic residue at position 6 of [Nle¹⁰]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation. Journal of Medicinal Chemistry, 42(15), 3004-3007. https://doi.org/10.1021/jm9807151

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 journal › Article

Gembitsky, DS, Murnin, M, Ötvös, FL, Allen, J, Murphy, RF & Lovas, S 1999, 'Importance of the aromatic residue at position 6 of [Nle¹⁰]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation', Journal of Medicinal Chemistry, vol. 42, no. 15, pp. 3004-3007. https://doi.org/10.1021/jm9807151

Gembitsky DS, Murnin M, Ötvös FL, Allen J, Murphy RF, Lovas S. Importance of the aromatic residue at position 6 of [Nle¹⁰]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation. Journal of Medicinal Chemistry. 1999 Jul 29;42(15):3004-3007. https://doi.org/10.1021/jm9807151

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

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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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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