2-phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

1 Selective activation of peripheral benzodiazepine receptors (PBRs) in adr enal cells and brain oligodendrocytes promotes steroidogenesis. Three 2-phe nyl-imidazo[1,2-a]pyridine derivatives (CB 34, CB 50 and CB 54) have now be en investigated with regard to their selectivity for PBRs and their ability to stimulate central and peripheral steroidogenesis in rats. 2 The three CB compounds (10(-10)-10(-4) M) potently inhibited the binding of the PER ligand [H-3]-PK 11195 to brain and ovary membranes in vitro, wit hout substantially affecting [H-3]-flunitrazepam binding to central benzodi azepine receptors. These compounds (10(-7)-10(-4) M) also had little or no marked effects on GABA-evoked Cl- currents in voltage-clamped Xenopus oocyt es expressing human alpha 1 beta 2 gamma 2S GABA(A) receptors. In addition, they failed to affect ligands binding to GABA(B), D-1/D-2 dopamine, muscar inic acetylcholine, N-methyl-D-aspartic acid and opiate receptors. 3 Intraperitoneal administration of CB compounds (3-50 mg kg(-1)) induced a dose-dependent increase in the concentrations of neuroactive steroids in p lasma and brain. The brain concentrations of pregnenolone, progesterone, al lopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+/-3, 126+/-14, 110+/-12 and 70+/-13% above control, respec tively, 30 to 60 min after injection of CB 34 (25 mg kg(-1)). CB 34 also in creased the brain concentrations of neuroactive steroids in adrenalectomize d-orchiectomized rats, although to a lesser extent than in sham-operated an imals, suggesting that CB compounds stimulate brain steroidogenesis indepen dently of their effects on peripheral tissues. 4 The increase in brain and plasma neurosteroid content induced by CB 34 wa s associated with a marked anticonflict effect in the Vogel test. Our resul ts indicate that the three CB compounds tested are specific and potent agon ists at peripheral benzodiazepine receptors, and that they stimulate steroi dogenesis in both the brain and periphery.