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Multitargeting of selected prostanoid receptors provides agents with enhanced anti‐inflammatory activity in macrophages
Author(s) -
Wang Jenny W.,
Woodward David F.,
Martos Jose L.,
Cornell Clive L.,
Carling Robert W.,
Kingsley Philip J.,
Marnett Lawrence J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-275610
Subject(s) - prostanoid , prostaglandin e2 receptor , receptor , chemistry , prostaglandin , cytokine , pharmacology , medicine , endocrinology , biology , biochemistry , agonist
A polypharmacologic approach to prostanoid based anti‐inflammatory therapeutics was undertaken in order to exploit both the anti‐ and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D 2 receptors (DPs) DP 1 (49) and DP 2 (558), prostaglandin E 2 receptors (EPs) EP 1 (266) and EP 4 (117), prostaglandin receptor (FP) (61), and thromboxane A 2 receptor (TP) (11) while sparing EP 2 , EP 3 , and prostaglandin I 2 receptors (IPs); K b values (in nanomoles) are given in parentheses. Compound 1 evoked a pronounced inhibition of cytokine/chemokine secretion from lipopolysaccharide or TNF‐α stimulated primary human macrophages. These cytokine/chemokines included cluster of designation 40 receptor (CD40), epithelial‐derived neutrophil‐activating protein 78 (ENA‐78), granulocyte colony stimulating factor (G‐CSF), granulocyte macrophage colony stimulating factor (GM‐CSF), IL‐8, IL‐18, monocyte chemotactic protein‐1 (CCL2) (MCP‐1), tissue plasminogen activator inhibitor (PAI‐1), and regulated on activation, normal T cell expressed and secreted (RANTES). In contrast, the inhibitory effects of most antagonists selective for a single receptor were modest or absent, and selective EP 2 receptor blockade increased cytokine release in some instances. Compound 1 also showed clear superiority to the cyclooxygenase inhibitors diclofenac and rofecoxib. These findings reveal that blockade of multiple prostanoid receptors, with absent antagonism of EP 2 and IP, may provide more effective anti‐inflammatory activity than global suppression of prostanoid synthesis or highly selective prostanoid receptor blockade. These investigations demonstrate the first working example of prostanoid receptor polypharmacology for potentially safer and more effective anti‐inflammatory therapeutics by blocking multiple proinflammatory receptors while sparing those with antiinflammatory activity.—Wang, J. W., Woodward, D. F., Martos, J. L., Cornell, C. L., Carling, R. W., Kingsley, P. J., Marnett, L. J. Multitargeting of selected prostanoid receptors provides agents with enhanced anti‐inflammatory activity in macrophages. FASEB J. 30, 394‐404 (2016). www.fasebj.org