Abstract
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.
MeSH terms
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Acenaphthenes
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Adrenocorticotropic Hormone / biosynthesis
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Animals
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Cells, Cultured
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Corticotropin-Releasing Hormone / metabolism
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Cyclic AMP / biosynthesis
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Drug Design
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Female
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Molecular Conformation
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Pituitary Gland, Anterior / cytology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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6-cyclopropylmethyl-2-(2,4-dichlorophenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene
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Acenaphthenes
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Heterocyclic Compounds, 3-Ring
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Pyrazoles
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Pyridines
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1
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Adrenocorticotropic Hormone
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Corticotropin-Releasing Hormone
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Cyclic AMP