主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
The translocator protein (TSPO, 18 kDa) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increases the level of neurosteroids.
The present study describes design, synthesis and investigation of anxiolytic-like effects of novel dipeptide TSPO ligand, originally designed on the basis of drug-based peptide design method [Gudasheva T.A. et al., J. Med. Chem., 1998] using Alpidem as non-peptide prototype. It is known that Alpidem demonstrates anxiolytic activity and its structure contains all the necessary TSPO ligands pharmacophore elements. Due to these arguments the dipeptide N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was designed as putative ligand.
The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in CD-1 mice. The activating effect on locomotor activity in mice was taken as a measure of the anxiolytic activity of compound.
GD-23 in the dosage range 0.05-1.0 mg/kg significantly (p<0.005) increased total locomotor activity of mice compared with control groups. GD-23 significantly (p <0.001) increased the percentage of time spent in the open arms of the maze in the dose range of 0.1-1.0 mg/kg. Anxiolytic effect of GD-23 was abolished by PK11195, a specific TSPO antagonist. It was found that by pretreatment with trilostane, a selective inhibitor of 3beta-HSD, or finasteride, a selective 5alpha-reductase inhibitor, anxiolytic effect of GD-23 was not registered. Results were evaluated as the ratio of the time spent in the open arms of maze to the total residence time of the animals in the open and closed arms. The obtained results demonstrate that the anxiolytic effect is mediated by interaction of the compound GD-23 with TSPO receptor.
The study of the relationship between structure and activity has shown that D,L- and L,D- diastereomers of GD-23 have no activity, the anxiolytic activity also disappears by replacing the C-amide group with the methyl ester or methylamide. Hence GD-23 can provide a basis for a new peptide class of fast anxiolytics without side effects of benzodiazepines.
This work was supported by RFBR, 17-0400861
