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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.

A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D2 dopamine receptor (DRD2) in a [3H]spiperone competition assay. All the herein described compounds consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on the DRD2–arylpiperazine complexes with the objective of exploring the receptor–ligand interactions and properties of the receptor binding site. The recently published crystal structure of DRD2 was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of DRD2 and therefore should contain a linker of 5 or 6 methylene groups long У овом раду је презентована синтеза 14 нових арилпиперазина и одређен је њихов афинитет везивања за Д2 допамински рецептор (DRD2) тестовима компетиције са [3H]спипероном. По својој хемијској структури ова једињења представљају супституисане бензимидазоле повезане са N-(2-метоксифенил)пиперазинским делом, линкерима разли- читих дужина. У циљу испитивања лиганд-рецептор интеракција и особина везивног места DRD2, урађена је докинг анализа новосинтетисаних једињења и симулација молекулске динамике, користећи кристалну структуру рецептора. Резултати добијени у овом раду указују да арилпиперазини високог афинитета остварују интеракције у ортостерном везивном месту и у екстензији ортостерног места везивања DRD2 и да стога треба да поседују линкер оптималне дужине, од 5 или 6 метиленских група.

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.

Series of eight novel 5-substituted derivatives of benzimidazole were synthesized by condensation of corresponding diamine with ethyl-4-[4-(2-chlorophenyl)piperazin-1-yl] butanoate in refluxing 4N hydrochloric acid. In vitro antibacterial activity against ten strains namely, Bacillus subtilis, Clostridium sporogenes, Streptosporangium longisporum, Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Proteus vulgaris and antifungal activity against two fungal strains namely, Candida albicans and Saccharomyces cerevisiae, were evaluated. Of all the compounds screened for activity 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-iodo-1H-benzimidazole and 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1H-benzimidazole were associated with higher antifungal activity than commercial drugs. [Projekat Ministarstva nauke Republike Srbije, br. 172032]

A series of 2-[4-(aryl substituted) piperazin-1-yl]- N -benzylacetamides were synthesized and the target compounds ( 3a–j ) were evaluated for atypical antipsychotic activity by studying apomorphine induced climbing behavior, 5-HTP induced head twitches behavior and catalepsy in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was assessed by calculating from a set of physicochemical properties using software programs. The test compounds ( 3a–j ) demonstrated good similarity values with respect to the standard drugs. Among them, compound 3b has emerged as an important lead compound showing potential atypical antipsychotic-like profile.

Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.

Eight new compounds with halogen atom introduced into the benzimidazole- 2-thione dopaminergic pharmacophore of 5-[2-(4-arylpiperazin-1-yl)ethyl]-1,3-dihydro- 2H-benzimidazole-2-thiones with the arylpiperazine part of the molecule being selected according to known structure-affinity requirements, have been synthesized. All the new compounds were evaluated for the in vitro binding affinity at the dopamine (DA) D1 and D2 and serotonin 5-HT1A receptors by the competitive radioassays, performed on synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi. All the new compounds were strong competitors for the binding of the radioligands to the D2 and 5-HT1A receptors, with the most active of them having 34 and 170 time higher affinity than non-halogenated congeners in the D2 DA receptor radioassays (compounds 9.1b and 9.2b, respectively). Divergently, these compounds were without significant affinities for the D1 DA receptors. .

Six newly synthesized heterocyclic (2-nitrophenyl)piperazines, with a specific structure of the heteroaryl group, whichmimics the catechol moiety of dopamine (benzimidazoles and substituted benzimidazoles), were evaluated for their binding affinity to rat dopamine (DA), serotonin (5-HT) and _1 receptors. All compounds with a benzimidazole group had a 5-HT2A/D2 receptors binding ratio characteristic for atypical neuroleptics (>1, pK i values). Compound 7c, 4-bromo-6-{2-_4-(2-nitrophenyl)piperazin- 1-yl_ethyl}-1H-benzimidazole, expressed higher affinities for all receptor classes than clozapine. Also, it exhibited the best characteristic for atypical neuroleptics and presents a compound with the best profile for further in vivo investigations.

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. (C) 2012 Elsevier B.V. All rights reserved.

The synthesis of a series of functionalized 1-Benzyl-3-[4-Aryl-1-piperazingl]carbonyl-1 H -Indoles 6(a-f), as a potential new class of bioactive ligands at D 4 receptors is reported. The synthetic strategy took place through a five steps sequence to provide indole amides 6(a-f) in 75-92% yield. Keywords : Indole, Arylpiperazines, dopaminergic activity. e-mail: hpessoa@ciq.uchile.cl INTRODUCTION The indole ring system is present in many biologically active medicinal agents and natural products 1-3 . The first synthesis of substituted indoles was conducted by Fischer and Jourdan as early as 1883, and since then the bicyclic heteroaromatic core has been the target of many synthetic approaches and reactivity studies. 4-7 Indoles are also prominent structural elements in the neurotransmitter serotonin, the antiinflammatory drug indomethacin and other molecules showing promise in the treatment of cardiovascular disease, erectile dysfunction, cancer and neurological conditions such as the Alzheimer’s disease

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 D(2) , 5-HT(2A) , and α(1) -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-HT(2A)/D(2) pK(i) 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.

A series of arylsulfonamides containing guanidine incorporated in the structure of secondary amines (piperidine, piperazine) was synthesized on SynPhase Lanterns and evaluated for 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors. The results demonstrated that N-alkyl-N'-dialkylguanidines displayed good 5-HT(7)/5-HT(1A) selectivity and may be regarded as promising structural core for development of 5-HT(7) ligands.

Novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives linked through an ethylene bridge to various phenylpiperazine groups were prepared for evaluation as 5-HT2A receptor antagonists. The target compounds 11a–p were prepared through the initial synthesis of the 2-chloroethyl intermediates 10a–d which were then reacted with the appropriate phenylpiperazines. All compounds were tested for their antagonistic activity on 5-HT2Areceptors using inhibition of 5-hydroxytryptophan(5-HTP)-induced head twitches in mice. Pharmacophore modeling study, based on a hypothetical pharmacophore template generated from a set of diverse known active ligands, revealed good fitting of the designed compounds to the generated hypothetical pharmacophore.

The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D 2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO 2 group in position 3 of arylpiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D 2 . Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D 2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket. Die Bindung von mehreren 1-Benzyl-4-arylpiperazin-Derivaten an den Dop-amin D2-Rezeptor wurde untersucht. Die Ergebnisse zeigen, daß die Interaktion des protonierten N1 des Piperazin-Rings mit Asp 86 (III.32) und „Edge-to-Face”-Interaktionen des aromatischen Rings des Acrylpiperazin-Anteils mit Phe 178 (VI.44), Trp 182 (VI.48) und Tyr 216 (VII.58) des Rezeptors die größte stabilisierende Kraft darstellt. Neben der Wasserstoffbrücken-Akzeptorgruppe in Position 2 von Phenylpiperazin kann der aromatische Ring eine zusätzliche Wasserstoffbrücke mit Trp 182 bilden. Große Substituenten in Position 4 wurden aufgrund sterischer Interaktionen mit Phe 179 (VI.44) nicht toleriert. Die Einführung der Elektronenakzeptorgruppe -NO2 in Position 3 von Arylpiperazin verminderte die Bindungsaffinität im Vergleich zu Phenylpiperazin 1, während die Elektronendonatorgruppe -OMe und der zweite aromatische Ring (Naphthyl) die Bindungsaffinität verstärkte. Dies kann mit einer bevorzugten „Edge-to-Face”-Interaktion bei Liganden mit stark negativem elektrostatischem Oberflächenpotential (ESP) im Zentrum des aromatischen Teils von Arylpiperazin erklärt werden. Neben Ionen- und Wasserstoffbrükken sind daher „Edge-to-Face”-Interaktionen maßgeblich mit an der Komplexbildung zwischen Arylpiperazin-Liganden und dem Dopamin D2-Rezeptor beteiligt. Phe 178 (VI.44), Trp 182 (VI.48) und Tyr 216 (VII.58) können als Teil einer zusätzlichen Dopamin D2-Rezeptortasche angesehen werden, die in den meisten GPRCs (G protein-coupled receptors) der AKlasse erhalten ist. Offensichtlich repräsentiert das Strukturmotiv von Arylpiperazin eine begünstigte Struktur, die an diese Tasche bindet.

5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-aryipiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D-1, D-2 and 5-HT1A, receptors examined. They expressed a rather high affinity for the D-2 doparnine receptor. The main features of ligand-D-2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N-1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy}-1,3-di hydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D-2 receptor and competition binding results was observed. (c) 2005 Elsevier SAS. All rights reserved.

Docking of several 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4- and 1-benzyl-arylpiperazines to the D(2) dopamine receptor (DAR) was examined. The binding pocket of the D(2) DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF(3), and NO(2)) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D(2) DAR.

The synthesis of a series of new n-propyl and n-butyl chain containing 1-aryl-piperazine derivatives of quinazolidin-4(3H)-one (7) 2-phenyl-2,3-dihydrophthalazine-1,4-dione (8) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9) as potential serotonin receptor ligands is described.