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J Med Chem. 2016 Jul 14;59(13):6329-43. doi: 10.1021/acs.jmedchem.6b00571. Epub 2016 Jun 30.

Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy.

Author information

1
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.
2
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Hai Ke Road, Shanghai 201203, China.
3
Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, China.
4
School of Pharmacy, Faculty of Health Sciences, Curtin University , Bentley, Perth, Western Australia 6102, Australia.
5
Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University , 3663 North Zhongshan Road, Shanghai 200062, China.

Abstract

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.

PMID:
27309376
DOI:
10.1021/acs.jmedchem.6b00571
[Indexed for MEDLINE]

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