Allosteric Functional Switch of Neurokinin A-Mediated Signaling at the Neurokinin NK2 Receptor: Structural Exploration

The neurokinin NK2 receptor is known to pre-exist in equilibrium between at least three states: resting-inactive, calcium-triggering, and cAMP-producing. Its endogeneous ligand, NKA, mainly induces the calcium response. Using a FRET-based assay, we have previously discovered an allosteric modulator...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2009-10, Vol.52 (19), p.5999-6011
Main Authors: Valant, Céline, Maillet, Emeline, Bourguignon, Jean-Jacques, Bucher, Bernard, Utard, Valérie, Galzi, Jean-Luc, Hibert, Marcel
Format: Article
Language:English
Subjects:
Allosteric Regulation
Animals
Biological and medical sciences
Calcium Signaling
Chemical Sciences
Cyclic AMP
Fluorescence Resonance Energy Transfer
Humans
Hydrocarbons, Aromatic - chemistry
Hydrocarbons, Aromatic - pharmacology
Life Sciences
Ligands
Medical sciences
Medicinal Chemistry
Neurokinin A - chemistry
Neurokinin A - metabolism
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmaceutical sciences
Pharmacology
Pharmacology. Drug treatments
Protein Conformation - drug effects
Receptors, G-Protein-Coupled
Receptors, Neurokinin-2 - chemistry
Receptors, Neurokinin-2 - drug effects
Receptors, Neurokinin-2 - metabolism
Signal Transduction - drug effects
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:The neurokinin NK2 receptor is known to pre-exist in equilibrium between at least three states: resting-inactive, calcium-triggering, and cAMP-producing. Its endogeneous ligand, NKA, mainly induces the calcium response. Using a FRET-based assay, we have previously discovered an allosteric modulator of the NK2 receptor that has the unique ability to discriminate among the two signaling pathways: calcium-signaling is not affected while cAMP signaling is significantly decreased. A series of compounds have been prepared and studied in order to better understand the structural determinants of this allosteric functional switch of a GPCR. Most of them display the same allosteric profile, with smooth pharmacomodulation. One compound however exhibits significantly improved modulatory properties of NKA induced signaling when compared to the original modulator.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900671k