Search

Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity and blood–brain barrier permeability. Compounds possessed N-benzylpiperidine and N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker. Retention parameters RM 0, b, and C0 were considered as the measures of lipophilicity. Besides, logD of the investigated compounds was determined chromatographically using standard compounds with known logPow and logD values at pH 11. Experimentally obtained lipophilicity parameters correlated well with in silico generated results, and the effect of the nature of the linker between two pharmacophores and substituents on the arylpiperazine part of the molecule was observed. As a result of drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were determined, suggesting that examined compounds could be potential candidates for further drug development. Principal component analysis was performed to obtain an insight into a grouping of compounds based on calculated structural descriptors, experimentally obtained values of lipophilicity, and AChE inhibitory activity.

Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most noted as a neurotransmitter, an activator of the utmost subtype family of G-protein- coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT receptors treat central nervous system diseases such as schizophrenia and depression. Recent advances in serotonin receptor structure research gave us several crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the antipsychotic drug aripiprazole (Abilify®). This discovery prompted us to evaluate a series of newly synthesized ligands for serotonergic activity since those arylpiperazine derivatives share minimal general structure with aripiprazole. The results of molecular docking analysis of unsubstituted starting substances encouraged us to propound further modifications of the tail and head parts of the parent molecules to maximize receptor binding affinity. Intrigued by the results of molecular analysis, all foreseen derivatives were synthesized. The pharmacological activity of all nine (5a and 6a are synthesized previously) compounds was assessed by the in vitro tests and in silico pharmacokinetics predictions for the most promising candidates. All tested ligands have improved affinity compering to parent compounds (10a and 11a), 8b and 9b expressed the best pharmacological profile with an improved binding affinity toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2-5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl] alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2–5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

5HT1A receptor targeting drugs have been used as the treatment for the many neuropsychiatric disorders, such as schizophrenia and depression. As a part of ongoing research, we designed series of new compounds that share arylpiperazine common structural motif with the 5HT1A receptor ligand aripiprazole. Receptor-ligand interactions were determined by the molecular docking simulations, revealing the positive impact of the phenyl substitution in the arylpiperazine part of the molecules. Nine selected compounds were synthesized in four reaction steps in high overall yields (59-73%). In vitro pharmacological evaluation of the synthesized compounds revealed three compounds (5b, 6b and 6c) with high 5HT1A binding affinity, comparable with aripiprazole (Ki 12.0, 4.8, 12.8, 5.6 nM, respectively). Compounds from b series, 5b and 6b, possess 2-methoxyphenyl substituents, while 6c possess 2,3-dichlorophenyl substituent in the arylpiperazine part of the molecule. The pharmacological results are therefore in accordance with the molecular docking simulations thus proving the rational design. Compounds 5c, 6b and 6c can be considered as the candidates for further evaluation as new, potential antidepressants.

Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be involved in the oxidative deamination of biogenic amines. While the use of MAO B inhibitors is already well-established for the treatment of Parkinson’s disease, recent reports suggest its involvement in certain types of brain tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron emission tomography (PET). Methodik/Methods A small series of fluorinated indanone derivatives was obtained via the O-alkylation or esterification starting with the commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or two steps. Binding affinities towards the human MAO isoenzymes were estimated in vitro by radioligand displacement. HL126 was selected for radiofluorination via its corresponding boronic acid pinacol ester. In vitro autoradiography of [18F]HL126 was performed in mice brain slices. In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and metabolism studies were performed in plasma and brain samples via radio-HPLC. Ergebnisse/Results The fluorinated indanone derivatives were synthesized in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126, was further selected for radiofluorination based on its high binding affinity towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %, high radiochemical purities (≥99 %) and molar activities in the range of 20 GBq/mmol. In vitro autoradiography showed a specific blockade with selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126 readily enters the brain. Some radiometabolites do cross the blood-brain barrier. Schlussfolgerungen/Conclusions Although metabolism studies with [18F] HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towa

Serotonin 5HT1a receptor belongs to a class of G-protein coupled receptors. It serves as a potential target for neurological disorders such as depression, anxiety etc. It is a well-known fact that N-arylpiperazine moiety is present in compounds with pronounced 5HT1a activity. Taking into account previously published results1 novel structures of N-{4-[2-(4- arylpiperazin-1-yl)ethyl]phenyl}arylamides (Figure 1.) were designed for target synthesis. Proposed modifications include: different position of hydroxyl group in aryl amide part of molecule and addition of methoxy and chloro substituents to the phenyl ring of parent compounds, since their introduction in the molecule leads to increased receptor affinity. New compounds were synthesized by acylation of N-arylpiperazines using 4- nitrophenylacetic acid. Obtained amides were converted in 1-(4-nitrophenethyl)-4- arylpiperazines using diborane in THF. Reduction of nitro compounds by Ra/Ni provided 1- (4-aminophenethyl)-4-arylpiperazines. Target arylamides were obtained by condensation 1- (4-aminophenethyl)-4-arylpiperazines with corresponding aryl acids in presence of propylphosphoric acid anhydride (PPAA) in DMF. All newly synthesized compounds were evaluated for their activity toward 5HT1a receptors by in vitro competitive displacement assay of [3H] 8-OH-DPAT. HEK cell line were used as a source of 5HT1a receptors. Introduction of 2-methoxy and 2,3-dichloro groups,as well as meta and para hydroxyl group in molecule resulted in increment of affinity toward 5HT1a receptors comparing to the parent compounds.

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 poka, 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 bi