Dopamine D2 receptor binding site study by newly synthesized 2-methoxyphenylpiperazine ligands

Poslednjih godina sve više ljudi oboleva od šizofrenije, depresije i drugih neuroloških poremećaja. Njihi izazivaju promene na nivou dopaminergičkog i serotonergičkog sistema u mozgu. Dizajn i sinteza dopaminergičkih i serotonergičkih liganada koji bi našli primenu u lečenju bolesti izazvanih disfunkcijom ovih receptorskih sistema u CNS, a čije korišćenje ne bi izazivalo negativne efekte je primaran zadatak naučnika u oblasti medicinske hemije. Poznavanje strukture receptora, odnosno mesta vezivanja liganada u receptoru, doprinelo bi bržem razvoju potencijalnih lekova. U okviru ove doktorske disertacije uspešno je sintetisano i okarakterisano 46 novih liganada. Ligandi su razvrstani u dve serije: ligandi sa piperidinskim prstenom u mostu između glave (benzil, benzoil, fenetil, fenacetil grupe sa odgovarajućim supstituentima) i repa (2-metoksifenilpiperazin) i ligandi sa različitom dužinom alkil mosta između glave (supstituisani benzimidazoli) i repa (2-metoksifenilpiperazin). Za sve novosintetisane ligande određen je farmakološki profil vezivanja za dopaminske D2, serotoninske 5HT2a i adrenergičke α1 receptore u testovima kompetitivnog vezivanja sa radioaktivno obeleženim ligandima. U seriji liganada sa piperidinskim prstenom u mostu između glave (benzil, benzoil, fenetil, fenacetil grupe sa odgovarajućim supstituentima) i repa (2-metoksifenilpiperazin) uočeno je da supstituisani ligandi pokazuju veći afinitet prema dopaminskim D2 receptorima nego nesupstituisani ligandi. Pored toga, ligandi sa većim stepenom fleksibilnosti (metilenski most između piperidinskog i piperazinskog prstena) pokazali su veći afinitet od rigidnih liganada (piperazinski prsten je direktno vezan za piperidinski prsten). Ova serija liganada pokazala je odsustvo ili slab afinitet prema serotoninskim 5HT2a receptorima. U seriji liganada sa različitom dužinom alkil mosta između benzimidazolskog dela i 2-metoksifenilpiperazina utvrđeno je da najveći afinitet prema dopaminskim D2 redceptorima pokazuju ligandi sa pet i šest ugljenikovih atoma u mostu. Izuzev dva liganda, ostala jedinjenja iz ove serije poseduju umeren afinitet vezivanja za serotoninske 5HT2a receptore. U radu je putem doking analize, pored ortosternog mesta vezivanja ispitano i mesto vezivanja dopaminskog D2 receptora koje čini druga ekstracelularna petlja (ecl2). Doking analiza predviđa da ligandi pored toga što ostvaruju aromatične interakcije sa aminokiselinskim ostacima u hidrofobnom džepu receptora Phe 386 (6.44), Trp 390 (6.48), Tyr 420 (7.43), formiraju i hidrofobne interakcije sa aminokiselinskim ostacima Phe 393 i His 397 koji se nalaze u ecl2. Takođe, preliminarna doking analiza liganada sa različitom dužinom alkil mosta između glave (supstituisani benzimidazoli) i repa (2-metoksifenilpiperazin), ukazuje na postojanje hidrofobnih interakcija između liganda i Ile 166, Leu 170, Ile 184, Phe 189, Val 111, Ile 398, His 397 iz regiona druge ekstracelularne petlje.Schizophrenia, depression and related neurological disorders are modern day diseases, caused by dopaminergic and serotonergic imbalances in the brain. Design and synthesis of dopaminergic and serotonergic ligands without side effects, which could find application in the treatment of these CNS disorders, is one of the main objectives of medicinal chemistry. Improved understanding of dopamine D2 receptor binding site would contribute to faster development of potential drugs. As a part of this thesis, 46 new ligands were synthesized and characterized. The ligands were grouped into two sets: ligands with a piperidine ring in the bridge between the head (benzyl, benzoyl, phenethyl, and phenylacetyl groups with different substituents) and the tail (2-methoxyphenylpiperazine) and ligands with different lengths of the alkyl bridge between the head (substituted benzimidazoles) and the tail (2-methoxyphenylpiperazine). All newly synthesized ligands were evaluated for D2, 5HT2a and α1 affinity in an in vitro competitive displacement assay using radiolabeled ligands. Among ligands with the piperidine ring in the bridge between the head (benzyl, benzoyl, phenethyl, phenylacetyl groups with different substituents) and the tail (2-methoxyphenylpiperazine), substituted ligands exhibited a higher affinity for dopamine D2 receptors. In addition, ligands with a greater degree of flexibility (a methylene bridge between the piperidine and piperazine rings) demonstrated a higher affinity compared to rigid ligands (the piperazine ring is bound directly to the piperidine ring). This series of ligands displayed no or low affinity for the serotonin 5HT2a receptors. Among ligands with different lengths of the alkyl bridge between the benzimidazole and 2-methoxyphenylpiperazine part of the molecule, highest affinity for the dopamine D2 receptor was demonstrated by ligands with five or six carbon atoms in the bridge. Compounds in this series, with the exception of two ligands, had a moderate binding affinity for the serotonin 5HT2a receptors. The docking analysis was used to examine the D2 orthosteric binding site and the alternative binding site formed by the second extracellular loop (ecl2). Preliminary docking analysis predicts that ligands, in addition to the interactions with Phe 386 (6.44), Trp 390 (6.48) and Tyr 420 (7.43) in the hydrophobic pocket of the orthosteric binding site, form hydrophobic interactions with Phe 393 and His 397, located in the ecl2. Likewise, the preliminary docking analysis of ligands with the different lengths of the alkyl bridge between the head (substituted benzimidazoles) and the tail (2-methoxyphenyl piperazine), indicated the existence of hydrophobic interactions between the ligands and Ile 166, Leu 170, Ile 184, Phe 189, Val 111, Ile 398 and His 397, located in the second extracellular loop (ecl2)

Синтетски пут за добијање 1,2,3,4-тетрахидрохиноксалинскo/пиперидинског трицикличног система

The synthetic route toward novel tricyclic, nitrogen-containing system is disclosed. Three novel compounds possessing structural features of 1,2,3,4-tetrahydroquinoxaline and decahydropyrido[3,4-b]pyrazine are synthesized starting from readily available precursors in six or seven steps, of which the last three or four steps respectively are diastereoselective. Key reaction steps include N-acylation, Hofmann rearrangement and ring-closing Buchwald– Hartwig reaction. Compounds trans-8, cis-12 and trans-12 are synthesized in order to prove that this novel, tricyclic system can be functionalized with various groups. Synthetic significance of this heterocyclic system lies in the possibility for the orthogonal functionalization of three different amino groups, allowing fine structural tuning.У овом раду представљена је синтеза новог трицикличног система који садржи азот. Три нова једињења код којих су комбиноване структурне карактеристике 1,2,3,4-тетрахидрохиноксалина и декахидропиридо[3,4-b]пиразина, добијена су полазећи од лако доступних прекурсора, у шест или седам фаза од којих су последње три или четири, редом, диастереоселективне. Кључне синтетичке трансформације укључују N-ациловање, Hofmann премештање и интрамолекулску Buchwald–Hartwig реакцију, као фазу у којој долази до циклизације. Једињења trans-8, cis-12 и trans-12 су синтетисана како би се представила могућност функционализације новог трицикличног система. Синтетички значај новог хетероцикличног система представљен је у могућности ортогоналне функционализације три различите амино групе, чиме се може постићи фино подешавање структуре

The influence of policies on the rural part of the Pannonian plain, case study: region of Vojvodina

In this article are given the opinions by Pannonia countryside inhabitants that belong to the Republic of Serbia about some characteristics of everyday policy. The opinions are gathered by poll which was distributed by e-mail to different areas of the Province of Vojvodina. Namely, 122 participants who filled the poll correctly estimated ten stances. They were formed on the basis of the themes about which the farmers have most often discussed. Special attention was directed to differences concerning the opinion of participants of different gender and age structure, activity and political engagement. Descriptive statistics, T-test and one-factor analysis of ANOVA variance have been used for establishing the differences and were complemented by Post-hoc Tukey test. This paper could be used for improvement of connections and relationships among the politicians, policy and countryside

Supplementary data for the article: Penjišević, J. Z.; Šukalović, V. V.; Andrić, D. B.; Roglić, G. M.; Šoškić, V.; Kostić-Rajačić, S. V. Synthesis, Biological, and Computational Evaluation of Substituted 1-(2-Methoxyphenyl)-4-(1-Phenethylpiperidin-4-Yl)Piperazines and 1-(2-Methoxyphenyl)-4-[(1-Phenethylpiperidin-4-Yl)Methyl]Piperazines as Dopaminergic Ligands. Archiv der Pharmazie 2016, 614–626. https://doi.org/10.1002/ardp.201600081

Supplementary material for: [https://doi.org/10.1002/ardp.201600081]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2286

The trends in maize and wheat production in the Republic of Serbia

The total area under cereals during 2018 remained at a long-term stable level of about 1.7 million hectares. Maize and wheat are the most important crops grown in the Republic of Serbia. In the structure of harvested areas under cereals, maize dominates (53%), followed by wheat (38%). The objective of this paper was to determine if there was a recognisable trend line for the production of these crops in the 2007-2018 period. The yield data (Area harvested (ha), Production (tonnes), Production (t/ha)) were collected from the Statistical Office of the Republic of Serbia. Calculations of relevant and valid trends using central tendency measures, dispersion measures, relative ratios and percentage growth were used for statistical data processing. During the observation period, the average annual growth in maize yield was 6.38%, while the average annual growth in wheat yield was slightly lower, 2.00%. However, it is not possible to create an appropriate trend line for any of the variables in order to predict a future time period, since the coefficient of determination is low.Ukupna poljoprivredna površina pod strnim žitima u 2018. godini nije puno varirala u odnosu na prethodne godine i iznosila je oko 1.7 miliona hektara. Kukuruz i pšenica predstavljaju najznačajnije biljne kulture koje se gaje u Republici Srbiji. U strukturi požnjevenih površina pod žitaricama kukuruz je dominirao sa čak 53% i bio je praćen od strane pšenice sa 38%. Cilj ovog rada bio je utvrditi postoji li prepoznatljiva linija trenda proizvodnje ovih kultura za period od 2007. do 2018. godine. Podaci o prinosu (požnjevena površina (ha), proizvodnja (u tonama), prinos (t/ha)) prikupljeni su od Republičkog zavoda za statistiku. Za statističku obradu podataka korišćeni su proračuni relevantnih i validnih kretanja primenom mera centralne tendencije, mera disperzije, relativnih pokazatelja i procentualnog rasta. Prosečni godišnji rast prinosa kukuruza u posmatranom periodu iznosi 6,38%, dok je za pšenicu prosečan godišnji rast u posmatranom periodu nešto manji i iznosi 2,00%. Međutim, ni za jednu od promenljivih nije moguće napraviti odgovarajuću liniju trenda, u cilju predviđanja za budući vremenski period, jer je koeficijent determinacije mali

Supplementary data for the article: Penjišević, J. Z.; Šukalović, V. V.; Andrić, D. B.; Roglić, G. M.; Novaković, I. T.; Šoškić, V.; Kostić-Rajačić, S. V. Synthesis, Biological Evaluation and Docking Analysis of Substituted Piperidines and (2-Methoxyphenyl)Piperazines. Journal of the Serbian Chemical Society 2016, 81 (4), 347–356. https://doi.org/10.2298/JSC151021097P

Supplementary material for: [https://doi.org/10.2298/JSC151021097P]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1937

1,1′-(Piperazine-1,4-di­yl)dipropan-2-ol

The asymmetric unit of the crystal contains one-fourth of the title compound, C10H22N2O2, with the centre of the piperazine ring located at a site of 2/m symmetry. The piperazine ring adopts a chair conformation. The methine and methylene C atoms of the 2-hydroxypropyl groups show symmetry-imposed disorder over two equally occupied and mutually exclusive sets of positions. Only intra­molecular O—H⋯N contacts are observed

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands

Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands