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: In 2020, it is already 43 years since Braestrup and Squires discovered 18 kDa translocator protein (TSPO), known until 2006 as "peripheral benzodiazepine receptor". During this time the functions of this receptor which is located on the outer membrane of mitochondria were studied in detail. One of the key functions of TSPO is the transfer of cholesterol from the outer to the inner mitochondrial membrane, which is the limiting stage in the synthesis of neurosteroids. TSPO is also involved in the transport of porphyrins, mitochondrial respiration, the opening of mitochondrial pores, apoptosis and cell proliferation. This review presents current information on the structure of TSPO, the mechanism of its participation in neurosteroidogenesis, as well as endogenous and synthetic TSPO ligands. Particular emphasis is placed on the analysis of approaches to the design of synthetic ligands and their neuropsychotropic activity in vitro and in vivo. The presented review demonstrates the promise of constructing new neuropsychotropic drugs in the series of TSPO ligands.

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:he 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.

Synthesis and selected properties of N substituted pyrrolo[2,1 c] 1,3 diazacycloalkano[1,2 a]pyrazinonesThe reactions of methyl α (2 formyl 1H pyrrol 1 yl)carboxylates with N substituted aliphatic 1,2 , 1,3 , and 1,4 diamines afford new pyrrole containing heterocyclic systems: 1,2,3,10b tetrahydroimidazo[1,2 a]pyrrolo[2,1 c]pyrazin 5(6H) ones, 1,3,4,11b tetrahydro 2H pyrrolo[2´,1´:3,4]pyrazino[1,2 a]pyrimidin 6(7H) ones, and 1,2,3,4,5,12b hexahydro pyrrolo[2´,1´:3,4]pyrazino[1,2 a][1,3]diazepin 7(8H) ones. The reduction of these compounds with different reagents was studied.* t 1 , 120-150 s; t 2 , 1 day; t 3 , 1 week. ** One isomer. Scheme 6R´ = Me, n = 1 (a); R´ = H, n = 2 (b) which was obtained by subtraction of the spectrum recorded within one week after the dissolution of crystalline compound 1j in CDCl 3 from the spectrum recorded immediately after the dissolution (CDCl 3 ), δ: 1.79 (d, H, H a (CH b )Ar, 2 J = 13.3 Hz); 2.77 (ddd, 1 H, H a C(2), 2 J 2a,2b = 12.0 Hz, 3 J 2a,3b = 11.4 Hz, 3 J 2a,3a = 8.7 Hz); 2.89 (ddd, 1 H, H b C(2), 2 J 2b,2a = 12.0 Hz, 3 J 2b,3b =8.0 Hz, 3 J 2b,3a = 2.1 Hz); 2.99 (d, 1 H, H b (CH a )Ar, 2 J = 13.3 Hz); 3.33 (ddd, 1 H, H a C(3), 2 J 3a,3b = 11.5 Hz, 3 J 3a,2a = 8.7 Hz, 3 J 3a,2b = 2.1 Hz); 3.47 (dd, 1 H, H a (CH b )Ph, 2 J = 14.0 Hz, 3 J = 4.2 Hz); 3.55 (ddd, 1 H, H b C(3), 2 J 3b,3a = = 11.5 Hz, 3 J 3b,2a = 11.4 Hz, 3 J 3b,2b = 8.0 Hz); 3.68 (dd, H b (CH a )Ph, 2 J = 14.0 Hz, 3 J = 4.2 Hz); 3.84 and 3.86 (both s, 3 H each, 2 OMe); 5.04 (t, 1 H, CHCH 2 Ph, 3 J = 4.2 Hz); 5.20 (s, 1 H, H(10b)); 6.21 (m, 1 H, H(10)); 6.39 (m, 1 H, H(9)); 6.54 (d, 1 H, H Ar (5), 3 J = 8.1 Hz); 6.67 (m, 1 H, H(8)); 6.74 (d, 1 H, H Ar (6), 3 J = 8.1 Hz); 6.90-7.11 (m, 6 H, Ph, H Ar (2)). The 1 H NMR spectrum of the second diastereomer of 1j, which was obtained by subtraction of the spectrum recorded immediately after the dissolution of crystalline compound 1j in CDCl 3 from the spectrum recorded within one week after the dissolution (CDCl 3 ), δ: 2.39 (ddd, 1 H, H a C(2), 2 J 2a,2b = 10.9 Hz, 3 J 2a,3b = 11.1 Hz, 3 J 2a,3a = 8.5 Hz); 3.05 (ddd, 1 H, H b C(2), 2 J 2b,2a = 10.9 Hz, 3 J 2b,3b =7.6 Hz, 3 J 2b,3a = 1.9 Hz); 3.22-3.39 (m, 4 H, CH 2 Ph, H a (CH b )Ar, H a C(3)); 3.59 (ddd, 1 H, H b C(3), 2