MOLECULAR-BASIS OF PERIPHERAL VS CENTRAL BENZODIAZEPINE RECEPTOR SELECTIVITY IN A NEW CLASS OF PERIPHERAL BENZODIAZEPINE RECEPTOR LIGANDS RELATED TO ALPIDEM

Alpidem (1), the anxiolytic imidazopyridine, has nanomolar binding aff inity for both the central benzodiazepine receptor (CBR) and the perip heral benzodiazepine receptor (PER). A novel class of PER ligands rela ted to alpidem has been designed by comparing the interaction models o f alpidem with PER and CBR. Several compounds in this class have shown high selectivity for PER vs CBR, and the selectivity has been discuss ed in terms of interaction models. The binding behavior of the three s elected compounds was extensively studied by competition and saturatio n assays, and the results suggest that they are capable of recognizing two sites labeled by [H-3]PK11195. The molecular structure of one of the most active compounds (4e) has been determined by X-ray diffractio n and compared with that of alpidem. Molecular modeling studies sugges t that the bioactive conformation of 4e is Likely to be very similar t o the conformation found in the crystal.