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J Med Chem. 2016 Feb 11;59(3):810-40. doi: 10.1021/acs.jmedchem.5b00982. Epub 2015 Sep 21.

Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

Author information

1
Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
2
Department of Medicinal Chemistry and Minnesota Supercomputing Institute for Advanced Computational Research, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.

Abstract

There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

PMID:
26390077
DOI:
10.1021/acs.jmedchem.5b00982
[Indexed for MEDLINE]

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