Neuropharmacological profile of peripheral benzodiazepine receptor agonists, DAA1097 and DAA1106

Receptor binding and behavioral profiles of N-(4-chloro-2-phenoxyphenyl)-N- (2-isopropoxybenzyl)acetamide (DAA1097) and N-(2,5-dimethoxybenzyl)-N-(5-fl uoro-2- phenoxyphenyl)acetamide (DAA1106), novel, selective agonists for th e peripheral benzodiazepine receptor (PBR) were examined. DAA1097 and DAA11 06 inhibited [H-3]PK 11195 binding to crude mitochondrial preparations of r at whole brain, with IC50 values of 0.92 and 0.28 nM. Likewise, DAA1097 and DAA1106 inhibited [H-3]Ro 54864 binding to the same mitochondrial preparat ion, with IC50 values of 0.64 and 0.21 nM. In contrast,DAA1097 and DAA1106 did not inhibit [H-3]-flunitrazepam, the central benzodiazepine receptor (C BR) ligand, binding to membranes of rat whole brain (IC50>10,000nM). Oral a dministration of DAA1097 and DAA1106 had anxiolytic effects in the mouse li ght/dark exploration test and in the rat elevated plus- maze test. Oral adm inistration of DAA1106, diazepam and buspirone but not DAA1097 significantl y increased sleeping time in hexobarbital-induced anesthesia in mice. The o rder of potency of potentiation of hexobarbital anesthesia was diazepam> bu spirone> DAA1106> DAA1097. Oral administration of DAA1097 and DAA1106 but n ot diazepam and buspirone did not affect spontaneous locomotor activity in mice. These findings indicate that DAA1097 and DAA1106 are PER selective li gands with potent anxiolytic-like properties, in laboratory animals.