Abstract
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
MeSH terms
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Animals
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Choroid Plexus / metabolism
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Frontal Lobe / metabolism
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In Vitro Techniques
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Models, Molecular*
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Pteridines / chemical synthesis*
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Pteridines / chemistry
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Pteridines / pharmacology
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Pyridazines / chemical synthesis*
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Pyridazines / chemistry
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Pyridazines / pharmacology
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Quantitative Structure-Activity Relationship*
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Radioligand Assay
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Rats
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Receptors, Corticotropin-Releasing Hormone / metabolism
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Swine
Substances
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CRF receptor type 2
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Pteridines
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Pyridazines
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1