Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor.
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.
Jiang
Jianxiong
J
Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA.
Ganesh
Thota
T
Du
Yuhong
Y
Thepchatri
Pahk
P
Rojas
Asheebo
A
Lewis
Iestyn
I
Kurtkaya
Serdar
S
Li
Lian
L
Qui
Min
M
Serrano
Geidy
G
Shaw
Renee
R
Sun
Aiming
A
Dingledine
Ray
R
D000494:Allosteric Regulation; D000818:Animals; D015374:Biosensing Techniques; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D031541:Fluorescence Resonance Energy Transfer; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D053758:Nanoparticles; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013329:Structure-Activity Relationship
D018696:Neuroprotective Agents; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D015232:Dinoprostone