Supplementary data for the article: Šegan, S.; Penjišević, J.; Šukalović, V.; Andrić, D.; Milojković-Opsenica, D.; Kostić-Rajačić, S. Investigation of Lipophilicity and Pharmacokinetic Properties of 2-(Methoxy)Phenylpiperazine Dopamine D2 Ligands. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 2019, 1124, 146–153. https://doi.org/10.1016/j.jchromb.2019.06.006

Supplementary material for: [https://doi.org/10.1016/j.jchromb.2019.06.006]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3696

Synthesis of novel 5-HT1A arylpiperazine ligands: Binding data and computer-aided analysis of pharmacological potency

Serotonin receptors modulate numerous behavioral and neuropsychological processes. Therefore, they are the target for the action of many drugs, such as antipsychotics, antidepressants, antiemetics, migraine remedies, and many others. The 5-HT1A receptors have been involved in the pathogenesis and treatment of anxiety and depression and represent a promising target for new drugs with reduced extrapyramidal side effects. In most antidepressants, a piperazine-based structural motif can be identified as a common moiety. Here we describe the synthesis, pharmacological, and in silico characterization of a novel arylpiperazines series with excellent 5-HT1A affinity. The final compounds, 4a, 8a, and 8b, were selected according to predictions of in silico pharmacokinetics, docking analysis, and molecular dynamics in conjunction with physical properties, and metabolic stability. The accentuated molecules could serve as a lead compound for developing 5-HT1A drug-like molecules for depression treatment

Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides

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)

Design, synthesis and pharmacological evaluation of N-{4-[2-(4-aryl-piperazin-1-yl)-ethyl]-phenyl}-arylamides

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

The Therapeutic Potential of 2-{[4-(2-methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles as Ligands for Alpha1-Adrenergic Receptor - Comparative In Silico and In Vitro Study

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.Supplementary material for: [https://cherry.chem.bg.ac.rs/handle/123456789/5182

Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography

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

The influence of dispersive interactions on the binding affinities of ligands with an arylpiperazine moiety to the dopamine D2 receptor

Several isosteric 1,3-dihydro-5-[2-(4-aryl-1-piperazinyl)ethyl]-2H-benzimidazole-2-thiones were used to investigate the interactions of different ligands with the binding site of the D2 receptor. Due to limitations of the simulation methods, docking analysis failed to show precisely the interactions that influence the binding affinity of the ligands. It is presumed that dispersive forces or more precisely edge-to-face interactions play an important role in the binding process, especially for the lipophilic part of the ligands. In order to confirm this hypothesis, ab initio calculations were applied on a model system in order to find the stabilization energies of potential edge-to-face interactions and then to correlate them with the ligand affinity. The obtained results indicate that there is a significant correlation between the strength of dispersive inter-actions and ligand affinity. It was shown that for the calculation of stabilization energies of modeled receptor–ligand complexes the Becke “half-and-half” hybrid DFT method can be used, thus speeding up the usually long calculation time and reducing the required computer strength

Pharmacological evaluation of selected arylpiperazines with atypical antipsychotic potential

Six active compounds, among previously synthesized and screened arylpiperazines, were selected and evaluated for the binding affinity to rat dopamine, serotonin and alpha(1) receptors. Two compounds with benztriazole group had a 5-HT2A/D-2 binding ratio characteristic for atypical neuroleptics ( gt 1, pK(i) values). Compound 2, 5-{2-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]ethyl}1H-benzotriazole, expressed clozapine-like in vitro binding profile at D-2, 5-HT2A and alpha1 receptors and a higher affinity for 5-HT1A receptors than clozapine. Also, it exhibited the noncataleptic behavioural pattern of atypical antipsychotics and antagonized d-amphetamine-induced hyperlocomotion in rats. (C) 2004 Elsevier Ltd. All rights reserved

JSCS–3899

The influence of dispersive interactions on the binding affinities of ligands with an arylpiperazine moiety to the dopamine D2 recepto