895010-72-7Relevant academic research and scientific papers
Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment
Jeong, Pyeonghwa,Kim, Soo-Kyung,Li, Quanjie,Oh, Su-jin,Son, Seonil,Chen, Guangju,Tan, Hongwei,Kim, Siwon,Park, Jong-Hyun,Park, Ki Duk,Kim, Yeo Ok,Yoon, Myung Ha,Kim, Yong-Chul,Goddard, William A.
, p. 1783 - 1794 (2019)
Gi-protein-biased agonists with minimal β-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (μ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel μ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi-protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the μ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.
ANAPLASTIC LYMPHOMA KINASE MODULATORS AND METHODS OF USE
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, (2008/06/13)
The present invention comprises compounds and pharmaceutical compositions comprising the compounds that are inhibitors of ALK. The invention also comprises methods of using the compounds and compositions to treat diseases mediated by ALK, including diseases such as cancer, immunological disorders, cardiovascular diseases, and other degenerative disorders.
