Abstract
We report the identification of substituted cis-bicyclo[3.3.0]-oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.
MeSH terms
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Alkenes / chemical synthesis*
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Alkenes / chemistry
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Alkenes / pharmacology
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Binding Sites
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Bridged Bicyclo Compounds / chemical synthesis*
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacology
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Cells, Cultured
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DNA-Binding Proteins / agonists*
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Fluorescence Resonance Energy Transfer
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Genes, Reporter
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Homeodomain Proteins / agonists*
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Humans
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Ligands
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Protein Structure, Tertiary
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics
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Stereoisomerism
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Steroidogenic Factor 1
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Structure-Activity Relationship
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Transcription Factors / agonists*
Substances
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Alkenes
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Aniline Compounds
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Bridged Bicyclo Compounds
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DNA-Binding Proteins
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GSK 8470
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Homeodomain Proteins
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Ligands
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NR5A1 protein, human
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NR5A2 protein, human
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Receptors, Cytoplasmic and Nuclear
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Steroidogenic Factor 1
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Transcription Factors
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nuclear receptor subfamily 0, group B, member 2