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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.


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Synthesis of homodimer 1: (i) CH3CN/H2O 50:50, NaHCO3 (cat), rt, 12 h. Compounds 2–9, 11, 13 were obtained under the same experimental conditions starting from the corresponding monomer.
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f1: Synthesis of homodimer 1: (i) CH3CN/H2O 50:50, NaHCO3 (cat), rt, 12 h. Compounds 2–9, 11, 13 were obtained under the same experimental conditions starting from the corresponding monomer.

Mentions: As far as ligand synthesis is concerned, homodimeric ligands with peptide nature, compounds 1–9, 11, 13, were obtained by linking via disulphide bridge two monomers in which a thiol moiety has been added at the C-terminal. Homodimeric compounds were generated by air oxidation of the monomer in the presence of NaHCO3 as catalyst41 (Fig. 1). Monomers were synthesized by solid phase peptide synthesis techniques, purified by preparative HPLC, solubilized in a mixture CH3CN/H2O 50:50 with the addition of NaHCO3 5% and then stirred in an open flask at room temperature. The reaction mixture was monitored by analytical HPLC and the oxidation goes to completion in about 12 h. Under the same analytical HPLC conditions, the dimeric derivatives showed an increase in retention time of about 1.5 min compared to the parent monomer.


Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands
Synthesis of homodimer 1: (i) CH3CN/H2O 50:50, NaHCO3 (cat), rt, 12 h. Compounds 2–9, 11, 13 were obtained under the same experimental conditions starting from the corresponding monomer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Synthesis of homodimer 1: (i) CH3CN/H2O 50:50, NaHCO3 (cat), rt, 12 h. Compounds 2–9, 11, 13 were obtained under the same experimental conditions starting from the corresponding monomer.
Mentions: As far as ligand synthesis is concerned, homodimeric ligands with peptide nature, compounds 1–9, 11, 13, were obtained by linking via disulphide bridge two monomers in which a thiol moiety has been added at the C-terminal. Homodimeric compounds were generated by air oxidation of the monomer in the presence of NaHCO3 as catalyst41 (Fig. 1). Monomers were synthesized by solid phase peptide synthesis techniques, purified by preparative HPLC, solubilized in a mixture CH3CN/H2O 50:50 with the addition of NaHCO3 5% and then stirred in an open flask at room temperature. The reaction mixture was monitored by analytical HPLC and the oxidation goes to completion in about 12 h. Under the same analytical HPLC conditions, the dimeric derivatives showed an increase in retention time of about 1.5 min compared to the parent monomer.

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.


Related in: MedlinePlus