CC BY
3DOI 10.24412/cl-37235-2024-1-80-86
NEW APPROACH FOR SYNTHESIS OF 1-AMINO-CYCLOPROPANE CARBOXYLIC ACID (ACC) DERIVATIVES AND EXPLORING THEM AS MODULATORS OF HUMAN N-METHYL-D-ASPARTATE (NMDA) RECEPTORS VIA DOCKING ANALYSIS
S. Bagdasaryan1'2, A. Grigoryan1'2'3, M. Sahradyan1, A. Mikaelyan2
Russian-Armenian (Slavonic) University 2Armenian National Agrarian University 3University of Tradition Medicine of Armenia sambagd55@gmail. com, anna.grigoryan@rau.am, mane.sahradian@gmail.com, aramrmik@yahoo.com
ABSTRACT
Substituted cyclopropane units hold significant importance and play a crucial role in wide range of natural compounds and its synthetic analogues for diverse biological activities. Particularly 1-aminocyclopropane carbox-ylic acid (ACC) is a non-protein amino acid naturally occurring in plants, playing a pivotal role in the biosynthesis of the plant hormone ethylene. In addition, it is well known, that ACC and their synthetic analogues display a diverse biological activity, including neuromodulator influence. Current research is devoted to the docking study of 1 -amino-2-hexylcyclopropane-1-carboxylic and 1-amino-2-phenylcyclopropane-1-carboxylic acids interactions with human N-Methyl-D-Aspartate (NMDA) receptors. In silico experiments employing cheminformatic methods have revealed the mod-ulatory activity of the mentioned compounds, which were synthesized using our own methodology. These findings hold significant potential for their future medical applications.
Keywords: N-methyl-D-aspartate, 1-Aminocyclopropane-1-carboxylic acid, cyclopropanation of 1,3-dihalides, neurotransmitters.
Introduction
The N-methyl-D-aspartate receptor (NMDAR or NMDA receptor) is extremely crucial for synaptic plasticity in the central nervous system, which is important for learning, and memory function. In addition, NMDAR dysfunction is responsible for various disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia and depression [1].
The multimeric construction of NMDAR includes the following subunits: GluN1, GluN2, and GluN3 [2]. They can have different isoforms and the combination of subunits determines the properties of the receptor. NMDAR activation re-
quires both agonist binding and depolarization of the postsynaptic membrane. Glutamate (Glu), glycine (Gly) and D-Ser are the main modulators that activate NMDAR. Glu binds to the receptor and opens an ion channel, allowing the influx of ions, especially calcium, into the neuron. The glutamate binding site is located on the GluN2 subunit of the NMDA receptor. Gly and D-ser, as co-agonists, help modulate the activity of NMDA receptors, promoting a balance between excitatory and inhibitory signals in the brain. Their binding site is located on the GluNl (less commonly GluN3) subunit of the NMDA receptor [3]. However, there is known other competitive or non-competitive modulators of NMDAR, which include the various natural and synthetic substances. That modulators display certain disadvantages or side-effects [4, 5]. That is why various synthetic analogues of natural compounds, have been studied for their ability to target NMDA receptors [6]. 1-Aminocyclopropane-l-carboxylic acid (ACC) is known for its NMDA receptor modulatory activity in animal organism. It provides a moderate level of NMDAR activation, depending on glutamate concentration, and reduces any excess signaling that may lead to neurotoxicity [7]. Some functional substituted derivatives of ACC are widely used as a potent therapeutic agent in various CNS dysfunctions. For example, (1R,2S)-2-phenylcyclopropyl-1-amine (tranylcypromine) is a well-known antidepressant. Tranylcypromine injection has a neuroprotective effect after NMDA-induced injury [8].
The development of accessible methods for the preparation of functionally substituted cyclopropanes is becoming the most important task of modern organic chemistry. In presented study functionally substituted cyclopropanes (FSC) have been in silico investigated for their potential NMDAR modulatory activity.
Materials and methods
The improved scheme of constructing of functionally substituted cyclopropanes derivatives was elaborated by the division of "Creation and quality control of agricultural preparations" at "Agrobiotechnology scientific center", branch of Armenian National Agrarian University foundation. The generalized scheme of synthesis of functionally substituted ACC consists of three stages:
1. ATRA trichloroacetic acid derivatives and/or other telogens (bromoform, tri-bromochloromethane, etc.) to unsaturated substrates (terminal olefins).
2. Dehalogenation-cyclopropanation of the resulting 1,3-dihalides with Zn/Cu pair (or other metals).
3. Transformations to corresponding aminoacides under the influence of potassium cyanate with the formation of intermediate isocyanates and alkoxycarbonyla-mino derivatives. (Fig. 1) [9].
Figure 1. The general scheme of the cyclization. R1=C4H9; C6H13; C8H17;
C6H5; CH=CH-C6H5 a) X=Cl, R2=CN; b) X=Cl, R2=COOMe(Et); c) X=Br, R2=H; d) X= Br, R2=Cl; Cu(I) Catalytic system : CuBr - 10 mol% to substrate, Piperidine (or another secondary ammine), Catalytic ligand/Co-Solvent - DMSO. Molar ratio 1):2):3) = 1 : 1 : 7-10/.
To explore the possible modulatory effect of the new synthetic ACC derivatives, methods of molecular modeling and computer analysis were used. Using cheminformatics protocols, four three-dimensional molecular models of the studied ligands were constructed: Glutamate, ACC, 1-amino-2-hexylcyclopropane-1-car-boxylic acid, 1-amino-2-phenylcyclopropane-1-carboxylic acid. Three-dimensional model of the studied target was taken from the RCSB database with the identification number PDB ID: 5H8F (human GluN1/GluN2A LBD).
Docking analysis was carried out using the AutoDock Vina and AutoDock Tools software packages. The analysis was performed independently 10 times using 20 initial conformations for each compound, with a virtual box volume not exceeding 27000 A. [10].
Results
ACC lacks optical activity, while the new synthesized derivatives have 2 chiral centers in their molecules and each of these compounds occurs in the form of 4 optical isomers (Fig. 2).
H,N
ACC l-amino-2-hexylcyclopropane-l-carboxylic acid
OH
1 -amino-2-phenylcyclopropane-1 -carboxylic acid
Figure 2. Molecular models of the studied ligands.
All presented compounds were tested in silico by the method of molecular docking. as a result of multiple iterations, it was revealed that 1S, 2S isomer of 1-amino-2-hexylcyclopropane-1-carboxylic is the most prospective modulator of NMDAR activity (Fig. 3).
Figure 3. Binding sites of ligands from left to right: Glutamte, ACC, (1S,2S)-1-amino-2-hexylcyclopropane-1-carboxylic acid.
The binding site and AG values of (1S, 2S)-1-amino-2-hexylcyclopropane-1-carboxylic acid to the appropriate target-protein is comparable to its natural modulator Glutamate and has lower AG values than well-known NMDAR modulator ACC (Table 1).
Table 1. Binding parameters.
Ligand Binding sites Affinity
Glutamate Arg120, Thr115, His87, Ser172, Thr173, Tyr213, Asp214 -6.2
Ligand Binding sites Affinity
ACC Arg120, Thr115, His87, Ser172, Thr173, Tyr213, Asp214 -5.2
(1S,2S)-1-amino-2-hexylcyclopropane-1 -carboxylic acid Arg120, Thr115, His87, Ser172, Tyr213, Asp214, Ser113, Gly171, Lys86, Asn170, Pro169, Val168 -6.2
Discussion
The technologies of the synthesis of functionally substituted derivatives of some biologically active substances are broadly used for the obtaining of compounds with targeted activity. That is one of the most common methods of drug design for novel medicines investigation and the in silico studies are the inseparable part of that research [11].
The results of the chemical experiments which were carried out have demonstrated the possibility to elaborate a novel and effective technological solution for the targeted synthesis of phenyl- and octyl- derivatives. The high yields were obtained during the described processes.
The previous microbiological research has demonstrated the antifungal properties 1-chloro-2-hexylcyclopropane-1-carboxylic acid. The fungicidal activity was detected.
Conclusion
An easy-to-implement technology for synthesis of functionally substituted cy-clopropane-carboxylic compounds was proposed during the experiments. The certain optical isomers of obtained novel compounds have shown significant activity via in silico experiments. Therefore, further in vitro research on the obtained compounds is desirable. Additionally, based on the experience gained from in silico and in vitro research, novel derivatives with improved target properties will be synthesized.
REFERENCES
1. Barry H., Byrne S., Barrett E., Murphy K.C., Cotter D. R. Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. "BJPsych Bulletin" - review article. 2015. V. 39. PP. 19-23.
2. Furukawa H., Singh S., Mancusso R., Gouaux E. Subunit arrangement and function in NMDA receptors. "Nature". 2005. V. 438(7065), PP. 185-192.
3. LiF., Tsien J. Memory and the NMDA receptors // "The New England Journal of Medicine". 2009. V. 361(3). PP. 302-303.
4. Hanson J.E., Yuan H., Perszyk R., Banke T., Xing H., Tsai M-C., Menniti F., Traynelis S. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry // "Neuro-psychopharmacology". 2024. V. 49. PP. 51-66.
5. TomekS., LaCrosse A., Nemirovsky N., OliveM. NMDA Receptor Modulators in the Treatment of Drug Addiction. Pharmaceuticals (Basel). 2013. V. 6(2). PP. 251-268.
6. Moore T., Alami A., Caleb G., Mattis D. Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review. "Pharmacotherapy". 2022. V. 42. PP. 567579.
7. GaoM., Kondo F., Murakami T., Xu J-W., Ma N., ZhuX., Mori K., Ishida T. 1 -Aminocyclo-propanecarboxylic Acid, an Antagonist of N-Methyl-D-Aspartate Receptors, Causes Hypotensive and Antioxidant Effects with Upregulation of Heme Oxygenase-1 in Stroke-Prone Spontaneously Hypertensive Rats. "Hypertens Res". 2007. V. 30 (3). PP. 249-57.
8. Bartova L., Vogl S., Stamenkovic M., Praschak-Rieder N., Naderi-Heiden A., Kasper S., Willeit M. Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases. "European Neuropsychopharmacology". 2015. V. 25, I. 11. PP. 2183-2184.
9. Mnatsakanyan A., Kocharyan D., Torosyan, G., Vardanyan, A., Mikaelyan A. Preparation of substituted cyclopropane carboxylic acids from organohalogen acids, "Vestnik NPUA". 2008. V. 76. PP. 825-830.
10. Багдасарян А.Б., БабаянБ.Г., УнанянЛ.С., Григорян А.М., Микаэлян А.Р. Сравнительный анализ оценки антибактериальной активности имидов и аминосолей винной кислоты, методом молекулярного докинга. "WayScience". 2021. PP. 156-164.
11. Chang Y., Hawkins B., Du J., Groundwater P., Hibbs D., Lai F. Guide to In Silico Drug Design. Pharmaceutics. 2022. V. 15(1). PP. 49.
ИССЛЕДОВАНИЕ НОВЫХ ПРОИЗВОДНЫХ 1-АМИНОЦИКЛОПРОПАН КАРБОНОВОЙ КИСЛОТЫ (ACC) В КАЧЕСТВЕ МОДУЛЯТОРОВ ЧЕЛОВЕЧЕСКИХ РЕЦЕПТОРОВ N-МЕТИЛ-Б-АСПАРТАТА (NMDA) ПОСРЕДСТВОМ ДОКИНГ-АНАЛИЗА
С.А. Багдасарян1'2, A.M. Григорян1'2'3, М.Г. Саградян1, А.Р. Микаелян2
Российско-Армянский (Славянский) университет 2Национальный Аграрный университет Армении 3Университет Традиционной Медицины
АННОТАЦИЯ
Замещенные циклопропановые звенья имеют важное значение и играют решающую роль в широком спектре природных соединений и их синтетических аналогов, обладающих разнообразной биологической активностью. В частности, 1-аминоциклопропан карбоновая кислота (АСС) представляет собой небелковую аминокислоту, встречающуюся в природе в растениях и играющую ключевую роль в биосинтезе растительного гормона этилена. Кроме того, известно, что ACC и их синтетические аналоги обладают разнообразной биологической активностью, в том числе нейромодуляторным действием. Текущие исследования посвящены изучению докинг-взаимодействий
1-амино-2-гексилциклопропан-1-карбоновых и 1-амино-2-фенилцик-лопропан-1-карбоновых кислот с рецепторами №метил-Э-аспартата (ЫМОА) человека. Эксперименты т sШco с использованием хемин-форматических методов выявили модулирующую активность указанных соединений, синтезированных по собственной методике. Эти результаты имеют значительный потенциал для их будущего медицинского применения.
Ключевые слова: К-метил-Э-аспартат, 1-аминоциклопропан-1-кар-боновая кислота, циклопропанирование 1,3-дигалогенидов, нейроме-диаторы.
