Theoretical structure-activity studies of benzodiazepine analogues. Requirements for receptor affinity and activity.

Conformational and electronic properties of a series of 1,4-benzodiazepine analogues and their specific interaction with a model cationic receptor site have been calculated using both empirical energy and semiempirical molecular orbital methods. The aim of these studies was to identify molecular properties and modes of receptor interaction which are determinants of relative receptor affinities and pharmacological activities for these anxiolytics. Analogues with variations in key positions of the 7-membered (B) ring, at positions C7, C8, and C9 of the fused phenyl (A) ring, and at positions 2' and 4' of the phenyl (C) ring were examined. The results indicate that both active and inactive analogues have similar low-energy conformations, arguing against this property as a modulator of recognition at the receptor. However, calculated molecular electrostatic potentials together with explicit model receptor interactions allowed the deduction that interactions with three cationic receptor sites are required for high-affinity analogues. The specific cationic site interactions are postulated with electron-withdrawing groups at C7, the C2 = O1 group, and the imine nitrogen, N4. Moreover, interactions of N4 with a model cationic receptor site are enhanced by halogen substituents at C2', but only when the phenyl ring is rotated by 30 degrees toward a more planar conformer, corresponding to an induced conformational change. If this enhancement is important, a 2'-Cl substituent on more rigid analogues of the 1,4-benzodiazepines with increased co-planarity of the phenyl C-ring and the C1'--C5 = N4 plane should have an even greater differential effect on receptor affinity.