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

Abstract

3 Intraperitoneal administration of CB compounds (3 ± 50 mg kg 71 ) induced a dose-dependent increase in the concentrations of neuroactive steroids in plasma and brain. The brain concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+3, 126+14, 110+12 and 70+13% above control, respectively, 30 to 60 min after injection of CB 34 (25 mg kg 71 ). CB 34 also increased the brain concentrations of neuroactive steroids in adrenalectomized-orchiectomized rats, although to a lesser extent than in sham-operated animals, suggesting that CB compounds stimulate brain steroidogenesis independently of their e ects on peripheral tissues. 4 The increase in brain and plasma neurosteroid content induced by CB 34 was associated with a marked anticon¯ict e ect in the Vogel test. Our results indicate that the three CB compounds tested are speci®c and potent agonists at peripheral benzodiazepine receptors, and that they stimulate steroidogenesis in both the brain and periphery.

Brain Steroidogenesis Mediates Ethanol Modulation of GABAAReceptor Activity in Rat Hippocampus

“…A, Pathway in glial cells of the hippocampus for the biosynthesis of the neurosteroid 3␣,5␣-THP (3␣-hydroxy-5␣-pregnan-20-one or allopregnanolone) from cholesterol. Translocation of cholesterol on the inner part of mitochondria, the first rate-limiting step in neurosteroid synthesis, is performed by several proteins, among others, the PBR, which in our experimental protocol was activated by the selective agonist CB34 (Serra et al, 1999). Finasteride, also used in our experiments, inhibits the enzyme 5␣-reductase, thus blocking the conversion of progesterone to 5␣-DHP and the formation of 3␣,5␣-THP.…”

“…Exposure of hippocampal slices to the PBR-selective agonist CB34, the systemic administration of which elicits a marked increase in both the plasma and brain concentrations of neuroactive steroids in rats (Serra et al, 1999), resulted in a time-and concentrationdependent increase in mIPSC amplitude (Fig. 4 A, C,E).…”

“…We compared the effects of ethanol with those of the neurosteroid precursor progesterone and of CB34 (see Fig. 1), a selective and high-affinity agonist of the peripheral benzodiazepine receptor (PBR) and stimulator of neurosteroidogenesis (Serra et al, 1999). In fact, PBRs are found primarily on the outer mitochondrial membrane, where they promote neurosteroidogenesis by facilitating cholesterol translocation into the mitochondria and are extremely abundant in steroidogenic endocrine tissues, including the brain (Gavish et al, 1999) (Fig.…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…Further SAR and structure-selectivity relationship (SSR) research helped explore the effects of modifying the alkyl groups attached to the amide functionality and resulted in the synthesis of an extended series of 2-phenyl-imidazo[1,2-a]-pyridine derivatives [66]. In 1999, three lead compounds from this series, (CB 54), were investigated for their agonistic effect on brain and plasma neurosteroid concentrations in normal and adrenalectomized-orchiectomized (ADX-ORX) rats [67]. CB34, CB 50 and CB 54 all competed with [ 3 H]PK 11195 for binding to membrane preparations of rat cerebral cortex and displayed IC 50 values of 1.03, 3.04 and 1.54 nM respectively (PK 11195, IC 50 = 1.43 in the same assay) [67].…”

“…In 1999, three lead compounds from this series, (CB 54), were investigated for their agonistic effect on brain and plasma neurosteroid concentrations in normal and adrenalectomized-orchiectomized (ADX-ORX) rats [67]. CB34, CB 50 and CB 54 all competed with [ 3 H]PK 11195 for binding to membrane preparations of rat cerebral cortex and displayed IC 50 values of 1.03, 3.04 and 1.54 nM respectively (PK 11195, IC 50 = 1.43 in the same assay) [67]. All three ligands were shown to stimulate steroidogenesis in rats which was indicated by elevated cortical concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydro-deoxycorticosterone (THDOC).…”