Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands

Iredia D. Iyamu, Wei Lv, Neha Malik, Rama K. Mishra, Gary E. Schiltz*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations


The sigma-1 and sigma-2 receptors have been shown to play important roles in CNS diseases, cancer, and other disorders. These findings suggest that targeting these proteins with small-molecule modulators may be of important therapeutic value. Here we report the development of a new class of tetrahydroindazoles that are highly potent and selective ligands for sigma-1. Molecular modeling was used to rationalize the observed structure-activity relationships and identify key interactions responsible for increased potency of the optimized compounds. Assays for solubility and microsomal stability showed this series possesses favorable characteristics and is amenable to further therapeutic development. The compounds described herein will be useful in the development of new chemical probes for sigma-1 and to aid in future work therapeutically targeting this protein.

Original languageEnglish (US)
Pages (from-to)1824-1835
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number9
StatePublished - May 1 2019


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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