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Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2010 Feb 02; Vol. 107 (5), pp. 2307-12. Date of Electronic Publication: 2010 Jan 14. - Publication Year :
- 2010
-
Abstract
- Activation of the Galphas-coupled EP2 receptor for prostaglandin E2 (PGE(2)) 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 microM (i) potentiated the cAMP response to a low concentration of PGE(2) by > 50%; (ii) had no effect on EP4 or beta2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE(2) 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 PGE(2) on EP2 receptors 4- to 5-fold at 10 to 20 microM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE(2) receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE(2) released in a cell-injury setting is neuroprotective.
- Subjects :
- Allosteric Regulation
Animals
Biosensing Techniques
Cyclic AMP metabolism
Dinoprostone metabolism
Drug Evaluation, Preclinical
Fluorescence Resonance Energy Transfer
Hippocampus drug effects
Hippocampus metabolism
In Vitro Techniques
Nanoparticles
Neurons drug effects
Neurons metabolism
Neuroprotective Agents chemistry
Rats
Rats, Inbred SHR
Receptors, Prostaglandin E, EP2 Subtype
Structure-Activity Relationship
Neuroprotective Agents pharmacology
Receptors, Prostaglandin E agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 107
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 20080612
- Full Text :
- https://doi.org/10.1073/pnas.0909310107