Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family

BMC Clinical Pharmacology

Ye Fang²  Robert Levenson¹  Elizabeth Tran²  Haiyan Sun²  Megan Morse¹ 

[1] Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA;Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, NY, USA

关键词: Label-free biosensor;    Functional selectivity;    Opioid receptor;   

Others  :  860625
DOI  :  10.1186/2050-6511-14-17

 received in 2012-06-05, accepted in 2012-10-31,  发布年份 2013

【 摘 要 】

Background

In vitro pharmacology of ligands is typically assessed using a variety of molecular assays based on predetermined molecular events in living cells. Many ligands including opioid ligands pose the ability to bind more than one receptor, and can also provide distinct operational bias to activate a specific receptor. Generating an integrative overview of the binding and functional selectivity of ligands for a receptor family is a critical but difficult step in drug discovery and development. Here we applied a newly developed label-free integrative pharmacology on-target (iPOT) approach to systematically survey the selectivity of a library of fifty-five opioid ligands against the opioid receptor family. All ligands were interrogated using dynamic mass redistribution (DMR) assays in both recombinant and native cell lines that express specific opioid receptor(s). The cells were modified with a set of probe molecules to manifest the binding and functional selectivity of ligands. DMR profiles were collected and translated to numerical coordinates that was subject to similarity analysis. A specific set of opioid ligands were then selected for quantitative pharmacology determination.

Results

Results showed that among fifty-five opioid ligands examined most ligands displayed agonist activity in at least one opioid receptor expressing cell line under different conditions. Further, many ligands exhibited pathway biased agonism.

Conclusion

We demonstrate that the iPOT effectively sorts the ligands into distinct clusters based on their binding and functional selectivity at the opioid receptor family.

【 授权许可】

   
2013 Morse et al.; licensee BioMed Central Ltd.

【 图 表 】

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