scholarly journals The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5132
Author(s):  
Tatiana A. Gudasheva ◽  
Olga A. Deeva ◽  
Andrey S. Pantileev ◽  
Grigory V. Mokrov ◽  
Inna V. Rybina ◽  
...  
Keyword(s):  
Amino Acid ◽  
Dose Range ◽  
Anxiolytic Effect ◽  
Anxiolytic Activity ◽  
Translocator Protein ◽  
Activity Relationship ◽  
Amino Acid Residues ◽  
Inner Mitochondrial Membrane ◽  
Design Synthesis ◽  
Rate Limiting Step

The translocator protein (TSPO, 18 kDa) plays an important role in 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 the design, synthesis and investigation of anxiolytic-like effects of a series of N-acyl-tryptophanyl-containing dipeptides. These novel dipeptide TSPO ligands were designed with the original drug-based peptide design strategy using alpidem as non-peptide prototype. The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in outbred laboratory mice ICR (CD-1). Dipeptide GD-102 (N-phenylpropionyl-l-tryptophanyl-l-leucine amide) in the dose range of 0.01–0.5 mg/kg intraperitoneally (i.p.) has a pronounced anxiolytic activity. The anxiolytic effect of GD-102 was abolished by PK11195, a specific TSPO antagonist. The structure–activity relationship study made it possible to identify a pharmacophore fragment for the dipeptide TSPO ligand. It was shown that l,d-diastereomer of GD-102 has no activity, and the d,l-isomer has less pronounced activity. The anxiolytic activity also disappears by replacing the C-amide group with the methyl ester, a free carboxyl group or methylamide. Consecutive replacement of each amino acid residue with glycine showed the importance of each of the amino acid residues in the structure of the ligand. The most active and technologically available compound GD-102, was selected for evaluation as a potential anxiolytic drug.

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

2019 ◽  
Vol 15 (4) ◽  
pp. 383-399 ◽  
Author(s):  
Tatiana A. Gudasheva ◽  
Olga A. Deeva ◽  
Grigory V. Mokrov ◽  
Alina S. Dyabina ◽  
Milada A. Yarkova ◽  
...  
Keyword(s):  
Open Field ◽  
Design Method ◽  
Anxiolytic Effect ◽  
Benzodiazepine Receptor ◽  
Anxiolytic Activity ◽  
Translocator Protein ◽  
In Vivo Studies ◽  
Inner Mitochondrial Membrane ◽  
New Compounds

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.

Design, synthesis, and pharmacological activity of new pyrrolo[1,2-a]pyrazine translocator protein (tspo) ligands

2021 ◽  
Vol 17 ◽  
Author(s):  
Grigory Mokrov ◽  
Andry Pantileev ◽  
Milada Yarkova ◽  
Tatiana Gudasheva ◽  
Sergei Seredenin
Keyword(s):  
Dose Range ◽  
Cycloaddition Reaction ◽  
Pharmacophore Model ◽  
Anxiolytic Activity ◽  
Translocator Protein ◽  
Design Synthesis ◽  
Docking Analysis ◽  
Promising Target ◽  
New Compounds ◽  
Modelling Methods

Background: Translocator protein 18 kDa (TSPO) is a promising target for the creation of effective and safe neuropsychotropic drugs. The ligands of TSPO exhibit anxiolytic, antidepressant, neuroprotective and other activities without the side effects of benzodiazepines. Methods: New TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives were designed using calculated pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out by two schemes using [3+3]-cycloaddition reaction of 2-azidoacrylic acid derivatives with pyrrolphenylketone as a key stage. The anxiolytic activity of new substances has been established using open field test with flash. Results: Several synthesized N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives significantly increased the total motor activity of Balb/c mice compared to the control. The structure-activity relationship was investigated. The most effective compound was found to be GML-11 (N-benzyl-N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamide), which had anxiolytic action in the dose range from 0.001 to 0.100 mg/kg (Balb/c, i.p.). This compound is two orders of magnitude higher in dose activity than all other pyrrolo[1,2-a]pyrazine TSPO ligands. Conclusion: Molecular modelling methods allowed us to create new TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides with high anxiolytic activity.

Design, Synthesis and Pharmacological Characterization of Endomorphin Analogues with Non-Cyclic Amino Acid Residues in Position 2

2010 ◽  
Vol 106 (2) ◽  
pp. 106-113 ◽  
Author(s):  
Renata Perlikowska ◽  
Jakub Fichna ◽  
Anna WyrÄ™bska ◽  
Jeroen Poels ◽  
Jozef Vanden Broeck ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Residues ◽  
Pharmacological Characterization ◽  
Design Synthesis

scholarly journals Identification of Amino Acid Residues within the N-Terminal Domain of EspA That Play a Role in EspA Filament Biogenesis and Function

2008 ◽  
Vol 190 (6) ◽  
pp. 2221-2226 ◽  
Author(s):  
Mona P. Singh ◽  
Robert K. Shaw ◽  
Stuart Knutton ◽  
Mark J. Pallen ◽  
Valerie F. Crepin ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Protein Stability ◽  
Type Iii Secretion ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Terminal Region ◽  
Translocator Protein ◽  
Amino Acid Residues ◽  
And Function

ABSTRACT Enteropathogenic Escherichia coli employs a filamentous type III secretion system, made by homopolymerization of the translocator protein EspA. In this study, we have shown that the N-terminal region of EspA has a role in EspA's protein stability, interaction with the CesAB chaperone, and filament biogenesis and function.

The design, synthesis, in vitro biological evaluation and molecular modeling of novel benzenesulfonate derivatives bearing chalcone moieties as potent anti-microtubulin polymerization agents

RSC Advances ◽  
2015 ◽  
Vol 5 (30) ◽  
pp. 23767-23777 ◽  
Author(s):  
Yu-Ning Shen ◽  
Lin Lin ◽  
Han-Yue Qiu ◽  
Wen-Yan Zou ◽  
Yong Qian ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Modeling ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Amino Acid Residues ◽  
Design Synthesis

Binding mode of compound 6b with microtubule (PDB code: 1SA0). (a) 2D diagram of the interaction between compound 6b and amino acid residues of colchicine site nearby. (b) 3D diagram of compound 6b inserted in microtubulin colchicine site.

scholarly journals Role of Asp104 in the SHV β-Lactamase

2006 ◽  
Vol 50 (12) ◽  
pp. 4124-4131 ◽  
Author(s):  
Christopher R. Bethel ◽  
Andrea M. Hujer ◽  
Kristine M. Hujer ◽  
Jodi M. Thomson ◽  
Mark W. Ruszczycky ◽  
...  
Keyword(s):  
Amino Acid ◽  
Catalytic Efficiency ◽  
Saturation Mutagenesis ◽  
Amino Acid Residues ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Threefold Increase ◽  
Rate Limiting ◽  
Hydrolysis Of

ABSTRACT Among the TEM-type extended-spectrum β-lactamases (ESBLs), an amino acid change at Ambler position 104 (Glu to Lys) results in increased resistance to ceftazidime and cefotaxime when found with other substitutions (e.g., Gly238Ser and Arg164Ser). To examine the role of Asp104 in SHV β-lactamases, site saturation mutagenesis was performed. Our goal was to investigate the properties of amino acid residues at this position that affect resistance to penicillins and oxyimino-cephalosporins. Unexpectedly, 58% of amino acid variants at position 104 in SHV expressed in Escherichia coli DH10B resulted in β-lactamases with lowered resistance to ampicillin. In contrast, increased resistance to cefotaxime was demonstrated only for the Asp104Arg and Asp104Lys β-lactamases. When all 19 substitutions were introduced into the SHV-2 (Gly238Ser) ESBL, the most significant increases in cefotaxime and ceftazidime resistance were noted for both the doubly substituted Asp104Lys Gly238Ser and the doubly substituted Asp104Arg Gly238Ser β-lactamases. Correspondingly, the overall catalytic efficiency (k cat/Km ) of hydrolysis for cefotaxime was increased from 0.60 ± 0.07 μM−1 s−1 (mean ± standard deviation) for Gly238Ser to 1.70 ± 0.01 μM−1 s−1 for the Asp104Lys and Gly238Ser β-lactamase (threefold increase). We also showed that (i) k 3 was the rate-limiting step for the hydrolysis of cefotaxime by Asp104Lys, (ii) the Km for cefotaxime of the doubly substituted Asp104Lys Gly238Ser variant approached that of the Gly238Ser β-lactamase as pH increased, and (iii) Lys at position 104 functions in an energetically additive manner with the Gly238Ser substitution to enhance catalysis of cephalothin. Based on this analysis, we propose that the amino acid at Ambler position 104 in SHV-1 β-lactamase plays a major role in substrate binding and recognition of oxyimino-cephalosporins and influences the interactions of Tyr105 with penicillins.

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