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

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.


Synthesis of non-peptide homodimers 19–25: (i) m-chloroperbenzoic acid, CH2Cl2, rt, 24 h; (ii) Titanium (V)isopropoxide; (ii) NaBH3CN, EtOH, rt, 2 h; (iv) Ethyl 7-bromoheptanoate, NaH, DMF, 60 °C 2 h; (v) aq NaOH 15% w/v, Dioxane, rt, 5 h; (vi) diamine, HATU, DIPEA, DMF, rt, 5 h; (vii) NH3, HATU, DMF, −20 °C to rt, 12 h.
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f3: Synthesis of non-peptide homodimers 19–25: (i) m-chloroperbenzoic acid, CH2Cl2, rt, 24 h; (ii) Titanium (V)isopropoxide; (ii) NaBH3CN, EtOH, rt, 2 h; (iv) Ethyl 7-bromoheptanoate, NaH, DMF, 60 °C 2 h; (v) aq NaOH 15% w/v, Dioxane, rt, 5 h; (vi) diamine, HATU, DIPEA, DMF, rt, 5 h; (vii) NH3, HATU, DMF, −20 °C to rt, 12 h.

Mentions: Ro 65-6570 dimeric ligands were synthesized following procedures depicted in Fig. 3. Ketone 16 was obtained by oxidation of acenaphtylene with m-chloroperbenzoic acid according with experimental conditions described in literature43. Reductive amination of compound 16 with the spiropiperidine 17 in the presence of titanium (IV) isopropoxide as Lewis acid and solvent provided the desired compound Ro 65-6570 that was employed in the next synthetic steps as racemate. The alkylation in position 3 of the 1,3,8-triaza[4.5]-spirodecane with an heptanoic acid moiety provided the desired arm for the further dimerization reaction. Dimerization of the NOP pharmacophore Ro 65-6570 was achieved reacting 18 with a series of linear aliphatic diamine that generated two symmetrical amide bonds and final dimeric compounds 19–25 with spacer length spanning from 18 to 24 atoms. Finally, intermediate 18 was also amidated (compound 26) in order to investigate the importance of the N-3 alkylation of Ro 65-6570 for NOP binding and activation.


Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands
Synthesis of non-peptide homodimers 19–25: (i) m-chloroperbenzoic acid, CH2Cl2, rt, 24 h; (ii) Titanium (V)isopropoxide; (ii) NaBH3CN, EtOH, rt, 2 h; (iv) Ethyl 7-bromoheptanoate, NaH, DMF, 60 °C 2 h; (v) aq NaOH 15% w/v, Dioxane, rt, 5 h; (vi) diamine, HATU, DIPEA, DMF, rt, 5 h; (vii) NH3, HATU, DMF, −20 °C to rt, 12 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Synthesis of non-peptide homodimers 19–25: (i) m-chloroperbenzoic acid, CH2Cl2, rt, 24 h; (ii) Titanium (V)isopropoxide; (ii) NaBH3CN, EtOH, rt, 2 h; (iv) Ethyl 7-bromoheptanoate, NaH, DMF, 60 °C 2 h; (v) aq NaOH 15% w/v, Dioxane, rt, 5 h; (vi) diamine, HATU, DIPEA, DMF, rt, 5 h; (vii) NH3, HATU, DMF, −20 °C to rt, 12 h.
Mentions: Ro 65-6570 dimeric ligands were synthesized following procedures depicted in Fig. 3. Ketone 16 was obtained by oxidation of acenaphtylene with m-chloroperbenzoic acid according with experimental conditions described in literature43. Reductive amination of compound 16 with the spiropiperidine 17 in the presence of titanium (IV) isopropoxide as Lewis acid and solvent provided the desired compound Ro 65-6570 that was employed in the next synthetic steps as racemate. The alkylation in position 3 of the 1,3,8-triaza[4.5]-spirodecane with an heptanoic acid moiety provided the desired arm for the further dimerization reaction. Dimerization of the NOP pharmacophore Ro 65-6570 was achieved reacting 18 with a series of linear aliphatic diamine that generated two symmetrical amide bonds and final dimeric compounds 19–25 with spacer length spanning from 18 to 24 atoms. Finally, intermediate 18 was also amidated (compound 26) in order to investigate the importance of the N-3 alkylation of Ro 65-6570 for NOP binding and activation.

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.