Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor

• Authors: Jianxiong Jiang, Emory University; Thota Ganesh, Emory University; Yuhong Du, Emory University; Pahk Thepchatri, Emory University; Asheebo Rojas, Emory University; Iestyn Lewis, Emory University; Serdar Kurtkaya, Emory University; Lian Li, Emory University; Min Qui, Emory University; Geidy Serrano, Emory University; Renee Shaw, Emory University; Aiming Sun, Emory University; Raymond J Dingledine, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 107, Number 5
• Publisher: National Academy of Sciences | 2010-02-02, Pages 2307-2312
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1073/pnas.0909310107
• Subjects: Health Sciences, Pharmacology; Chemistry, General
• Keywords: excitotoxicity; neuronal injury; prostaglandin E2; time-resolved fluorescence resonance energy transfer; ultra high-throughput screening

Abstract

Activation of the Gαs-coupled EP2 receptor for prostaglandin E2 (PGE2) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 μM (i) potentiated the cAMP response to a low concentration of PGE2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE2 on EP2 receptors 4- to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE2 released in a cell-injury setting is neuroprotective.