Neuropharmacological profile of peripheral benzodiazepine receptor agonists, DAA1097 and DAA1106

Abstract

Receptor binding and behavioral profiles of N-(4-chloro-2-phenoxyphenyl)-N-(2-isopropoxybenzyl)acetamide (DAA1097) and N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106), novel, selective agonists for the peripheral benzocliazepine receptor (PBR) were examined. DAA1097 and DAA1106 inhibited [ 3H]PK 11195 binding to crude mitochondrial preparations of rat whole brain, with IC 50 values of 0.92 and 0.28 nM. Likewise, DAA1097 and DAA1106 inhibited [ 3H]Ro 5-4864 binding to the same mitochondrial preparation, with IC 50 values of 0.64 and 0.21 nM. In contrast, DAA1097 and DAA1106 did not inhibit [ 3H]-flunitrazepam, the central benzodiazepine receptor (CBR) ligand, binding to membranes of rat whole brain (IC 50 > 10,000nM). Oral administration of DAA1097 and DAA1106 had anxiolytic effects in the mouse light/dark exploration test and in the rat elevated plus- maze test. Oral administration of DAA1106, diazepam and buspirone but not DAA1097 significantly increased sleeping time in hexobarbital-induced anesthesia in mice. The order of potency of potentiation of hexobarbital anesthesia was diazepam > buspirone > DAA1106 > DAA1097. Oral administration of DAA1097 and DAA1106 but not diazepam and buspirone did not affect spontaneous locomotor activity in mice. These findings indicate that DAA1097 and DAA1106 are PBR selective ligands with potent anxiolytic-like properties, in laboratory animals.