Discriminatory synergistic effect of Trp-substitutions in superagonist [(Arg/Lys) 14, (Arg/Lys) 15]nociceptin on ORL1 receptor binding and activation

[(Arg/Lys) 14, (Arg/Lys) 15]Nociceptin is a superagonist of the ORL1 receptor. Similar synergistic potentiation occurred when Trp was incorporated at position 14, but not 15. ORL1 is an endogenous G protein-coupled receptor for neuropeptide nociceptin. [(R/K) 14, (R/K) 15]nociceptin is a superagonis...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-08, Vol.17 (15), p.5683-5687
Main Authors: Nishimura, Hirokazu, Li, Jinglan, Isozaki, Kaname, Okada, Kazushi, Matsushima, Ayami, Nose, Takeru, Costa, Tommaso, Shimohigashi, Yasuyuki
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antagonist
Arginine - chemistry
Basic amino acids
Biological and medical sciences
Lysine - chemistry
Medical sciences
Molecular Sequence Data
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Nociceptin
Nociceptin Receptor
Opioid Peptides - chemical synthesis
Opioid Peptides - chemistry
Opioid Peptides - pharmacology
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Protein Binding
Rats
Receptors, Opioid - agonists
Receptors, Opioid - metabolism
Superagonist
Synergistic potentiation
Tryptophan - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[(Arg/Lys) 14, (Arg/Lys) 15]Nociceptin is a superagonist of the ORL1 receptor. Similar synergistic potentiation occurred when Trp was incorporated at position 14, but not 15. ORL1 is an endogenous G protein-coupled receptor for neuropeptide nociceptin. [(R/K) 14, (R/K) 15]nociceptin is a superagonist that strongly activates the ORL1 receptor. We have previously found that substituting with Trp can reproduce the potentiation induced by Arg or Lys at position 14. In the present study, in order to ensure the effect of Trp-substitution on the activities of [(R/K) 14, (R/K) 15]nociceptin, we synthesized [W 14, (R/K) 15]nociceptin and [(R/K) 14, W 15]nociceptin. [W 14, (R/K) 15]nociceptin was found to exhibit threefold higher binding activity and 10-fold greater potency in a functional [ 35S]GTPγS functional assay as compared to wild-type nociceptin. However, when only Trp was placed in position 15, the resulting analogues, [(R/K) 14, W 15]nociceptin, showed only a moderate enhancement of binding and biological activity (2–3 fold in both). These results indicate that the placement of Trp at position 14, unlike at position 15, enhances in a synergistic fashion the interaction of nociceptin with the ORL1 receptor. The results indicate that specific interactions feasible for Arg/Lys and Trp in common must be there for aromatic residues in ORL1, thus forming a cation/π interaction or π/π hydrophobic interaction. The necessity for a favorable electrostatic interaction appears strict in position 15.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.06.015