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

dc.contributor.advisorRoglić, Goran
dc.contributor.otherŠukalović, Vladimir
dc.contributor.otherAndrić, Deana
dc.creatorPenjišević, Jelena
dc.date.accessioned2019-02-04T12:25:58Z
dc.date.available2019-02-04T12:25:58Z
dc.date.issued2016
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=4906
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:15361/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=48823823
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/8026
dc.identifier.urihttp://cer.ihtm.bg.ac.rs/handle/123456789/2570
dc.description.abstractPoslednjih godina sve više ljudi oboleva od šizofrenije, depresije i drugihneuroloških poremećaja. Njihi izazivaju promene na nivou dopaminergičkog iserotonergičkog 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 afinitetprema 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 dvaliganda, ostala jedinjenja iz ove serije poseduju umeren afinitet vezivanja zaserotoninske 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.sr
dc.description.abstractSchizophrenia, depression and related neurological disorders are modern daydiseases, 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 fordopamine 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 inthe 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 andthe 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).en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Хемијски факултетsr
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectdopaminski D2 receptorsr
dc.subjectdopamine D2 receptoren
dc.subject2-methoxyphenylpiperazineen
dc.subjectdocking analysisen
dc.subject2-metoksifenilpiperazinsr
dc.subjectdoking analizasr
dc.titleProučavanje mesta vezivanja dopaminskog D2 receptora novosintetisanim ligandima 2-metoksifenilpiperazinskog tipasr
dc.title.alternativeDopamine D2 receptor binding site study by newly synthesized 2-methoxyphenylpiperazine ligandsen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dcterms.abstractРоглић, Горан; Шукаловић, Владимир В.; Aндрић, Деана Б.; Пењишевић, Јелена З.; Проучавање места везивања допаминског Д2 рецептора новосинтетисаним лигандима 2-метоксифенилпиперазинског типа; Проучавање места везивања допаминског Д2 рецептора новосинтетисаним лигандима 2-метоксифенилпиперазинског типа;
dc.identifier.fulltexthttp://cer.ihtm.bg.ac.rs/bitstream/id/13645/2568-teza.pdf
dc.identifier.fulltexthttp://cer.ihtm.bg.ac.rs/bitstream/id/8889/2568.pdf
dc.type.versionpublishedVersion


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