Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding

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Abstract

NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation.

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Acknowledgments

The authors would like to thank Ms. Nancy Tsou for growing diffractable crystals of 1, Dr. Rodney Bednar, Ms. Wei Lemaire, and Mr. Joe Bruno for determining binding potencies of key compounds, and Dr. Charles Ross and Ms. Joan Murphy for high resolution mass spectral analyses.

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