TY - JOUR
T1 - Importance of the aromatic residue at position 6 of [Nle10]neurokinin A(4-10) for binding to the NK-2 receptor and receptor activation
AU - Gembitsky, Dmitry S.
AU - Murnin, Mark
AU - Ötvös, Ferenc L.
AU - Allen, James
AU - Murphy, Richard F.
AU - Lovas, Sándor
PY - 1999/7/29
Y1 - 1999/7/29
N2 - 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.
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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U2 - 10.1021/jm9807151
DO - 10.1021/jm9807151
M3 - Article
C2 - 10425111
AN - SCOPUS:0033614975
VL - 42
SP - 3004
EP - 3007
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -