Deana Andrić

Structure–retention relationship study of arylpiperazines by linear multivariate modeling

A quantitative structure-retention relationship study has been performed to correlate the retention of 33 newly synthesized arylpiperazines with their molecular characteristics, using thin-layer chromatography. Principal component analysis followed by multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS) was performed to identify the most important factors, to quantify their influences, and to select descriptors that best describe the behavior of the compounds investigated. The best statistical performance was achieved by applying PLS regression, leading to the lowest value of the standard error (root mean square errors of calibration of 0.159 and cross-validated value RMSE cross-validation=0.231 units), followed by the PCR (root mean square errors of calibration=0.195 and RMSE cross-validation=0.305) and MLR (R(adj)(2)=0.9499, F=102.017, mean square error=0.052 and predicted residual error sum of squares=2.23). Two factors of the highest influence: surface tension and hydrophilic-lipophilic balance appear as the part of obtained models. In addition, polar surface area and hydrophilic surface area are included by both PLS and PCR models. Moreover, logP has been added to the PLS model. Besides, PCR model includes following descriptors: hydrogen bond acceptor, hydrogen bond donor and LUMO energy, whereas topological descriptors: connectivity indices 0 and 2, and valence index 3 are included in the MLR model.

Introduction of a methyl group in α- or β-position of 1-heteroarylethyl-4-phenyl-piperazines affects their dopaminergic/serotonergic properties

1‐(2‐Heteroarylalkyl)‐4‐phenylpiperazines containing methyl group in either the α‐ or the β‐position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5‐HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D1 receptor‐selective), spiperone (D2 receptor‐selective), and 8‐OH‐DPAT (5‐HT1A receptor‐selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D1 receptor. Introduction of the methyl group into the β‐position of the parent molecules increased the affinity for the D2 receptor (10b—13b), and decreased the affinity for the 5‐HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8‐OH‐DPAT. Most potent of the newly synthesized compounds in [3H]spiperone assay were compounds (±)6‐[1‐methyl‐2‐(4‐phenylpiperazin‐1‐yl)‐ethyl]‐1,4‐dihydroquinoxaline‐2,3‐dione (10b), Kd = 6.0 nM and (±)5‐[1‐methyl‐2‐(4‐phenylpiperazin‐1‐yl)‐ethyl]‐1,3‐dihydrobenzoimidazol‐2‐thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in α‐position (10a—13a) of the parent molecules expressed a decreased affinity for the D2 receptor, while the affinity for the 5‐HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds ((14—17) run in the same binding assays as references.

Interactions of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5-hydroxytryptamine 5HT1A receptors

It is suggested that the ratio of dopamine D(2) to 5-hydroxytryptamine 5-HT(1A) activity is an important parameter that determines the efficiency of antipsychotic drugs. Here we present the synthesis of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas and their structure-activity relationship studies on dopamine D(2) and 5-hydrohytryptamine 5-HT(1A) receptors. It was shown that ligand selectivity and affinity strongly depends on their topology and the presence of a pyridyl group in the head of molecules. Molecular modeling studies using homology modeling and docking simulation revealed a rational explanation for the ligand behavior. The observed binding modes and receptor-ligand interactions provided us with a clue for optimizing the optimal selectivity towards 5-HT(1A) receptors.

The mechanisms responsible for neuroprotective capacity of arylpiperazine dopaminergic ligands against cell death induced by sodium nitroprusside

A group of sixteen arylpiperazines had been previously synthesized and evaluated for atypical antipsychotic activity. Here we examined these compounds for their neuroprotective capacity. The affinity and agonist/antagonist action of the arylpiperazines at dopamine hD(2S) receptors were determined in vitro on membranes from stably transfected CHO-hD(2S) cell line. The assays for cell viability and antioxidative capacity (total glutathione and total superoxide dismutase activity), amount of nitric oxide and superoxide radicals, as well as influence on prosurvival pathways (Akt and ERK), were performed on the human neuroblastoma cell line SH-SY5Y. Cell death was induced by oxidative or nitrosative stress, or by growing cells in the medium deprived of serum. Only four of the arylpiperazines exhibited notable neuroprotection against cell death induced by sodium nitroprusside. Two of these arylpiperazines induced elevations of pAkt, while two other compounds reduced the levels of pErk, whereas these actions are considered to support the cell survival. The benzimidazole heteroaryl-group, that mimics catechol moiety of the dopamine molecule, might be the prerequisite structure for the neuroprotective action of these ligands. It is postulated that neuroprotection was acquired also by elevation of endogenous glutathione or total superoxide dismutase activity.

Planar chromatography of some 1-arylpiperazines behaving as dopaminergic ligands

The chromatographic behavior of fourteen 1-arylpiperazine derivatives has been studied by thin-layer chromatography on both silica gel and RP-18 silica gel. Unmodified silica gel was used as polar stationary phase in combination with monocomponent and binary non-polar mobile phases. Binary mobile phases comprising mixtures of methanol, acetone, or dioxane (as organic modifiers) and water were used with RP-18 silica for studies of the chromatographic behavior of the compounds under reversed-phase conditions. An approximately linear relationship was obtained between RM values and the amount of organic modifier in the mobile phases employed. The effect of mobile phase composition on the retention of the substances is discussed, as is the selectivity of the chromatographic systems used. Separation mechanisms are proposed on the basis of the results obtained.

Pharmacological Evaluation of Halogenated and Non-halogenated Arylpiperazin-1-yl-ethyl-benzimidazoles as D2 and 5-HT2A Receptor Ligands

Five groups of previously synthesized and initially screened non‐substituted and 4‐halogenated arylpiperazin‐1‐yl‐ethyl‐benzimidazoles were estimated for their in‐vitro binding affinities at the rat D2, 5‐HT2A, and α1‐adrenergic receptors. Among all these compounds, 2‐methoxyphenyl and 2‐chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4‐halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5‐HT2A/D2 pKi binding ratios slightly above or less than 1, while only 4‐chloro‐6‐(2‐{4‐[3‐(trifluoromethyl)phenyl]piperazin‐1‐yl}ethyl)‐1H‐benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non‐cataleptic action in rats and prevents d‐amphetamine‐induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency.

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides

Affinity chromatography was used to identify potential cellular targets that are responsible for neuroprotective activity of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides. Active and inactive representatives of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides bearing an extended linker were synthesized and immobilized on an agarose‐based matrix. This was followed by the identification of specifically bound proteins isolated out of the whole rat brain extract. Inducible flavoprotein NAD(P)H:quinone oxidoreductase (NQO1) was identified as candidates for cellular targets.

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.

Sixteen new 1‐(2‐methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines were synthesized to be used as probes for mapping the dopamine D2 receptor (D2DAR) arylpiperazine binding site. All compounds were evaluated for their affinity toward D2DAR in an in vitro competitive displacement assay. The most active one was 1‐(2‐methoxyphenyl)‐4‐{[1‐(3‐nitrophenethyl)piperidin‐4‐yl]methyl}piperazine (25) with an affinity of Ki = 54 nM. Docking analysis was conducted on all herein described compounds, whereas molecular dynamic simulation was performed on ligand 25 to establish its mode of interaction with D2DAR. Two possible docking orientations are proposed; the one with a salt bridge between the piperidine moiety and Asp114 of D2DAR is more stable.