G Protein Selectivity @ EP2 Recepotor Agonist

Structural optimization and structure–functional selectivity relationship studies of G protein-biased EP2 receptor agonists

 

http://dx.doi.org/10.1016/j.bmcl.2016.03.110

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Abstract

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure–functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.

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Graphical abstract

Keywords

• Prostaglandin;
• EP2;
• Agonist;
• Biased ligand;
• Structure–functional selectivity relationship

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© 2016 Elsevier Ltd. All rights reserved.