Design, Synthesis and Anxiolytic Activity Evaluation of N-Acyltryptophanyl- Containing Dipeptides, Potential TSPO Ligands.

Autor:	Gudasheva TA; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation., Deeva OA; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation., Mokrov GV; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation., Dyabina AS; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation., Yarkova MA; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation., Seredenin SB; Federal State Budgetary Institution 'Research Zakusov Institute of Pharmacology' (FSBI 'Zakusov Institute of Pharmacology'), Moscow, Russian Federation.
Jazyk:	angličtina
Zdroj:	Medicinal chemistry (Shariqah (United Arab Emirates)) [Med Chem] 2019; Vol. 15 (4), pp. 383-399.
DOI:	10.2174/1573406415666181119164846
Abstrakt:	Background: The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects. Methods: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze. Results: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05-1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride. Conclusion: A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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