THE CRYSTAL STRUCTURES OF SOME BENZODIAZEPINES AND BENZAZEPINES AS NONPEPTIDE CHOLECYSTOKININ RECEPTOR LIGANDS. Nancy N. Tsou, Karst Hoogsteen, James P. Springer, and Richard G. Ball, Merck Research Laboratories, P. O. Box 2000, Rahway, New Jersey 07065-0900, USA

A series of 1,4-benzodiazepine and novel benzazepine derivatives are reported as high affinity cholecystokinin (CCK) antagonists. The gastrointestinal hormone cholecystokinin¹ is found both in the gut and in the central nervous system. Two principle CCK receptor subtypes have been identified: CCK-A (alimentary canal) and CCK-B (brain). The CCK-A antagonists are believed to provide a new therapeutic agent for the treatment of irritable bowel syndrome and the CCK-B antagonists as a palliative for anxiety disorders.

Thirteen structures determined in our laboratory by single crystal X-ray diffraction studies are discussed here. All thirteen structures are either 1-methyl-2-oxo-1 ,4-benzodiazepines or 1-methyl-2-oxo-1 benzazepines and can be classified into three different groups: 1,3,5-trisubstituted benzazepines, 1,5-disubstituted benzodiazepines, and 1,3,5-trisubstituted benzodiazepines. Discussion of these structures will encompass structure motifs common to the structures, conformation of substituents and the relationship of structure and biological activity. These types of compounds are poorly represented in the structural literature with only a single similar compound in the Cambridge database.

¹Dethloff L. A. and De La Iglesia F. A., Cholecystokinin Antagonists - a Toxicologic Perspective, Drug Metab. Rev., 24(2), 267 ( 1992).