Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management.
J Med Chem
; 64(1): 890-904, 2021 01 14.
Article
in English
| MEDLINE | ID: covidwho-997768
ABSTRACT
The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Triazoles
/
Receptors, sigma
/
Pain Management
Type of study:
Etiology study
/
Experimental Studies
Limits:
Animals
/
Humans
Language:
English
Journal:
J Med Chem
Journal subject:
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jmedchem.0c01964
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