In:
ChemMedChem, Wiley, Vol. 14, No. 20 ( 2019-10-17), p. 1783-1794
Abstract:
G i ‐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 G i ‐protein‐biased compound, 1‐{5‐(3‐chlorophenyl)‐7,8‐dimethoxy‐3‐[4‐(methylsulfonyl)benzyl]‐3 H ‐pyrazolo[3,4‐ c ]isoquinolin‐1‐yl}‐ N , N ‐dimethylmethanamine, showed an EC 50 value of 179 n m 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201900418
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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