SYNTHESIS, BIOLOGICAL-ACTIVITY, AND SARS OF PYRROLOBENZOXAZEPINE DERIVATIVES, A NEW CLASS OF SPECIFIC PERIPHERAL-TYPE BENZODIAZEPINE RECEPTOR LIGANDS

The ''peripheral-type'' benzodiazepine receptor (PBR) has been reporte d to play a role in many biological processes. We have synthesized and tested a novel series of PBR ligands based on a pyrrolobenzoxazepine skeleton, in order to provide new receptor ligands. Several of these n ew compounds proved to be high affinity and selective ligands for PBR, and benzoxazepines 17f and 17j were found to be the most potent ligan ds for this receptor to have been identified to date. The SAR and the molecular modeling studies detailed herein delineated a number of stru ctural features required for improving affinity. Some of the ligands w ere employed as ''molecular yardsticks'' to probe the spatial dimensio ns of the lipophilic pockets L1 and L3 in the PBR cleft and to determi ne the effect of occupation of L1 and L3 with respect to affinity, whi le other C-7 modified analogues provided information specifically on t he hydrogen bonding with a putative receptor site H1. The new pyrrolob enzoxazepines were tested in rat cortex, a tissue expressing high dens ity of mitochondrial PBR, and exhibited IC50 and K-i values in the low nanomolar or subnanomolar range, as measured by the displacement of [ H-3]PK 11195 binding. A subset of the highest affinity ligands was als o found to have high affinities for [H-3]PK 11195 and [H-3]Ro 5-4864 b inding in rat adrenal mitochondria. All the ligands in this subset are stimulators of steroidogenesis having similar potency and extent of s timulation as PK 11195 and Ro 5-4864 of steroidogenesis in the mouse Y -1 adrenocortical cell line.