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Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands

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ABSTRACT

The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay. Both structure- and conformation-activity studies were performed. Results demonstrated that dimerization did not modify the pharmacological activity of both peptide and non-peptide pharmacophores. Moreover, when dimeric compounds were obtained with low potency peptide pharmacophores, dimerization recovered ligand potency. This effect depends on the doubling of the C-terminal address sequence rather than the presence of an additional N-terminal message sequence or modifications of peptide conformation.

No MeSH data available.


(a) Superposition of the ten lowest energy conformers of peptide 11. Structure models were superimposed using the backbone heavy atoms. Spacer position is indicated by a black ball. (b) Lowest energy conformer of family #1 structure. H-bond in the message region was evidenced as dotted line.
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f5: (a) Superposition of the ten lowest energy conformers of peptide 11. Structure models were superimposed using the backbone heavy atoms. Spacer position is indicated by a black ball. (b) Lowest energy conformer of family #1 structure. H-bond in the message region was evidenced as dotted line.

Mentions: Further NOE’s observed between the aromatic protons of Phe1 and Phe4, and the up-field shift of the aromatic proton signals of Phe1 demonstrate the spatial proximity of these aromatic rings. Using the NOE derived data as input, structure calculations by restrained simulated annealing gave the conformers of peptide 11 shown in Fig. 5. Structures display a well defined C-terminal region (backbone rmsd 0.10 Å for residues 6–12) and analysis of the ensemble dihedral angles (Table S6, Supporting Information) provides the presence of canonical α-helix from residue 7 to 10 flanked by distorted β-turns48 (type IV, i.e. they are not included in any canonical beta-turn structure) along residues 5–8 and 8–11.


Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands
(a) Superposition of the ten lowest energy conformers of peptide 11. Structure models were superimposed using the backbone heavy atoms. Spacer position is indicated by a black ball. (b) Lowest energy conformer of family #1 structure. H-bond in the message region was evidenced as dotted line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382891&req=5

f5: (a) Superposition of the ten lowest energy conformers of peptide 11. Structure models were superimposed using the backbone heavy atoms. Spacer position is indicated by a black ball. (b) Lowest energy conformer of family #1 structure. H-bond in the message region was evidenced as dotted line.
Mentions: Further NOE’s observed between the aromatic protons of Phe1 and Phe4, and the up-field shift of the aromatic proton signals of Phe1 demonstrate the spatial proximity of these aromatic rings. Using the NOE derived data as input, structure calculations by restrained simulated annealing gave the conformers of peptide 11 shown in Fig. 5. Structures display a well defined C-terminal region (backbone rmsd 0.10 Å for residues 6–12) and analysis of the ensemble dihedral angles (Table S6, Supporting Information) provides the presence of canonical α-helix from residue 7 to 10 flanked by distorted β-turns48 (type IV, i.e. they are not included in any canonical beta-turn structure) along residues 5–8 and 8–11.

View Article: PubMed Central - PubMed

ABSTRACT

The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay. Both structure- and conformation-activity studies were performed. Results demonstrated that dimerization did not modify the pharmacological activity of both peptide and non-peptide pharmacophores. Moreover, when dimeric compounds were obtained with low potency peptide pharmacophores, dimerization recovered ligand potency. This effect depends on the doubling of the C-terminal address sequence rather than the presence of an additional N-terminal message sequence or modifications of peptide conformation.

No MeSH data available.