Document Report Card

ID: ALA1156054

Journal: J Med Chem

Title: Allosteric functional switch of neurokinin A-mediated signaling at the neurokinin NK2 receptor: structural exploration.

Authors: Valant C, Maillet E, Bourguignon JJ, Bucher B, Utard V, Galzi JL, Hibert M.

Abstract: 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.

CiteXplore: 19746979

DOI: 10.1021/jm900671k