Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment

Title
Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment
Authors
박기덕박종현김시원정평화김수경Quanjie Li오수진Hongwei Tan김여옥윤명하김용철William A. Goddard, IIISeonil SonGuangju Chen
Issue Date
2019-10
Publisher
CHEMMEDCHEM
Citation
VOL 14, NO 20-1794
Abstract
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‐ 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‐ coupled receptors.
URI
http://pubs.kist.re.kr/handle/201004/70446
ISSN
1860-7179
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