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

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 -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.

• Authors: Pyeonghwa Jeong, Soo-Kyung Kim, Quanjie Li, Su-Jin Oh, Seonil Son, Guangju Chen, Hongwei Tan, Siwon Kim, Jong-Hyun Park, Ki Duk Park, Yeo Ok Kim, Myung Ha Yoon, Yong-Chul Kim, William A Goddard 3rd
• Journal: ChemMedChem (ChemMedChem) Vol. 14 Issue 20 Pg. 1783-1794 (10 17 2019) ISSN: 1860-7187 [Electronic] Germany
• PMID: 31359587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Analgesics, Opioid
• Ligands
• Methylamines
• Receptors, Opioid, mu
• Formaldehyde

Topics

• Analgesics, Opioid (chemistry, pharmacology)
• Animals
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Evaluation, Preclinical
• Formaldehyde (administration & dosage)
• Humans
• Ligands
• Methylamines (chemistry, pharmacology)
• Molecular Docking Simulation
• Molecular Structure
• Pain (chemically induced, drug therapy)
• Rats
• Receptors, Opioid, mu (agonists)
• Structure-Activity Relationship