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

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• 作者：Cline Valant ; Emeline Maillet ; Jean-Jacques Bourguignon ; Bernard Bucher ; Valrie Utard ; Jean-Luc Galzi ; Marcel Hibert
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 8, 2009
• 年：2009
• 卷：52
• 期：19
• 页码：5999-6011
• 全文大小：929K
• 年卷期：v.52,no.19(October 8, 2009)
• ISSN：1520-4804

文摘

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.