Abstract
Steric requirements of binding [Nle10]NKA(4-10) to NK-2 receptor were studied by introducing conformationally constrained amino acid analogs into its sequence. Two series of [Nle10]NKA(4-10) analogs were synthesized to investigate (i) the significance of a putative β-turn in the receptor-ligand interaction by insertion of either (S)- or (R)-Gly 8{ANC-2}Leu9 γ-lactams to mimic a β-turn constraint, and (ii) the effect of hindered rotation in the Φ, χ1 and χ2 dihedral angle space of the crucially important Phe6 which was replaced systematically with d-Phe, d- and l-Tyr, as well as with their conformationally constrained analogs, Tic, HOTic and β-MePhe. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. The analog possessing only an (R)-Gly8{ANC-2}Leu9 constraint, had the same binding affinity as that of the parent peptide. The rank order of potency of the other analogs showed a cumulative effect of different structural modifications in decreasing the binding affinity, i.e., when changing the configuration of the lactam ring to S, replacing Phe6 with constrained analogs, Tic or β-MePhe, changing the configuration of the amino acid at position six to d, and introducing a hydroxyl group on the aromatic ring.
| Original language | English |
|---|---|
| Pages (from-to) | 329-336 |
| Number of pages | 8 |
| Journal | International Journal of Peptide Research and Therapeutics |
| Volume | 13 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jun 2007 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
Cite this
Synthesis and structure-activity relationship of [Nle10] neurokinin A (4-10) analogs with constraint in the backbone and at position six. / Ötvös, Ferenc; Gembitsky, Dmitry S.; Murphy, Richard F.; Lovas, Sándor.
In: International Journal of Peptide Research and Therapeutics, Vol. 13, No. 1-2, 06.2007, p. 329-336.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and structure-activity relationship of [Nle10] neurokinin A (4-10) analogs with constraint in the backbone and at position six
AU - Ötvös, Ferenc
AU - Gembitsky, Dmitry S.
AU - Murphy, Richard F.
AU - Lovas, Sándor
PY - 2007/6
Y1 - 2007/6
N2 - Steric requirements of binding [Nle10]NKA(4-10) to NK-2 receptor were studied by introducing conformationally constrained amino acid analogs into its sequence. Two series of [Nle10]NKA(4-10) analogs were synthesized to investigate (i) the significance of a putative β-turn in the receptor-ligand interaction by insertion of either (S)- or (R)-Gly 8{ANC-2}Leu9 γ-lactams to mimic a β-turn constraint, and (ii) the effect of hindered rotation in the Φ, χ1 and χ2 dihedral angle space of the crucially important Phe6 which was replaced systematically with d-Phe, d- and l-Tyr, as well as with their conformationally constrained analogs, Tic, HOTic and β-MePhe. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. The analog possessing only an (R)-Gly8{ANC-2}Leu9 constraint, had the same binding affinity as that of the parent peptide. The rank order of potency of the other analogs showed a cumulative effect of different structural modifications in decreasing the binding affinity, i.e., when changing the configuration of the lactam ring to S, replacing Phe6 with constrained analogs, Tic or β-MePhe, changing the configuration of the amino acid at position six to d, and introducing a hydroxyl group on the aromatic ring.
AB - Steric requirements of binding [Nle10]NKA(4-10) to NK-2 receptor were studied by introducing conformationally constrained amino acid analogs into its sequence. Two series of [Nle10]NKA(4-10) analogs were synthesized to investigate (i) the significance of a putative β-turn in the receptor-ligand interaction by insertion of either (S)- or (R)-Gly 8{ANC-2}Leu9 γ-lactams to mimic a β-turn constraint, and (ii) the effect of hindered rotation in the Φ, χ1 and χ2 dihedral angle space of the crucially important Phe6 which was replaced systematically with d-Phe, d- and l-Tyr, as well as with their conformationally constrained analogs, Tic, HOTic and β-MePhe. Competition binding experiments with [3H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. The analog possessing only an (R)-Gly8{ANC-2}Leu9 constraint, had the same binding affinity as that of the parent peptide. The rank order of potency of the other analogs showed a cumulative effect of different structural modifications in decreasing the binding affinity, i.e., when changing the configuration of the lactam ring to S, replacing Phe6 with constrained analogs, Tic or β-MePhe, changing the configuration of the amino acid at position six to d, and introducing a hydroxyl group on the aromatic ring.
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U2 - 10.1007/s10989-007-9087-y
DO - 10.1007/s10989-007-9087-y
M3 - Article
VL - 13
SP - 329
EP - 336
JO - International Journal of Peptide Research and Therapeutics
JF - International Journal of Peptide Research and Therapeutics
SN - 1573-3149
IS - 1-2
ER -