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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 (Abilify7#174;). 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). [ABSTRACT FROM AUTHOR]

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a–c) and the corresponding acetylated derivatives was used (3a–c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a–c) and corresponding N-acetyl derivatives (3a–c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a–c and 3a–c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds. [ABSTRACT FROM AUTHOR]

Quipazine, first identified in the 1960s, has been the topic of >1000 published papers. On the basis of available 5-HT2 serotonin receptor radioligand binding data and various preclinical studies, it might be thought that quipazine bears the hallmarks of a classical hallucinogen or psychedelic agent - agents currently being examined for their potential use in treating certain neuropsychiatric disorders. Nevertheless, by definition, such agents require the availability of human data, which, in the case of quipazine, are lacking. Because quipazine is also a 5-HT3 receptor agonist, future human studies with this agent might prove problematic because 5-HT3 agonists are known to produce emesis. Nevertheless, continued investigation of novel quipazine analogs with modified pharmacological profiles might prove worthwhile. [ABSTRACT FROM AUTHOR]

Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a–c) and the corresponding acetylated derivatives was used (3a–c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a–c) and corresponding N-acetyl derivatives (3a–c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a–c and 3a–c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

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. [ABSTRACT FROM AUTHOR]

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. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172032]

In this work, a fragment-based labeling procedure was developed based on condensation reactions. Six 18F-labeled (arylpiperazinyl-butyl)oxindole derivatives were synthesized. These structures are interesting lead compounds with respect to development of a 5-HT7R PET tracer. They were radiolabeled in sufficient radiochemical yields, purities and molar activities for future in vivo evaluation in rodents. [ABSTRACT FROM AUTHOR]

• Six new salts with piperazine-related cations have been structurally determined. • Structural motifs are generated by charge-assisted hydrogen bonds. • The binding energies of cation-anion pairs have been estimated. • The trends have been plotted for binding energies versus proton-acceptor distances. Six new salts prepared by acid-base reactions containing 4-(2-methoxyphenyl)piperazin-1-ium cation (2-MeOPP) with simple organic-acid anions, namely pentafluorobenzoate, (I); (2 R ,3 R)-tartrate dihydrate, (II); succinate trihydrate, (III); or 4-phenylpiperazin-1-ium cation (PP) with 4-chlorobenzoate monohydrate, (IV); 3-chlorobenzoate monohydrate, (V) and succinate (VI) have been structurally characterised using single-crystal X-ray diffraction. Crystal-packing architectures have been described in the context of the supramolecular assemblies they form. The most important structural motifs are generated through hydrogen bonds between 2-MeOPP or PP cations and associated anions, assisted by their charges. To quantify these charge-assisted hydrogen bonds: (+)N−H····O(-) and (+)N−H····O, the binding energies of the ionic pairs have been calculated and compared. We considered a set of 72 ionic pairs of the structures analysed in this article and those published previously by our groups. As a result, we have plotted lines of trends found for DFT-binding energies vs normalised H···O proton···acceptor distances, and correlation between normalised geometrical parameters for aromatic and aliphatic anions. A comparison between DFT-energies and model pairwise energies (CE-B3LYP) has also been made. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT 7 receptor antagonist MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT 7 receptor as well as excellent drug – like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs. [ABSTRACT FROM AUTHOR]

Since the year 1993, when 5- HT7 receptor (5- HT7R) was discovered, there is no selective 5- HT7R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5- HT7R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by 'drug-likeness' estimation of the first series of selective and potent 5- HT7R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives ( 11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test ( FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5- HT7R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5- HT7 receptor. [ABSTRACT FROM AUTHOR]

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]

Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1 H -tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine ( 2i ), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC 50 = 158.7 nM for 5-HT, 99 nM for NE and 97.5 nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation. [ABSTRACT FROM AUTHOR]

A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D2receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2ligands. The most interesting because of their multireceptor profile were 8-piperidine (30–35) and 8-dipropylamine (45–47) analogs with four and five carbon aliphatic linkers. The selected compounds24,31,34,39,41,43,45, and46in the functionalin vitroevaluation for all targeted receptors showed significant partial D2agonist, partial 5-HT1Aagonist, and 5-HT2Aantagonist properties. The advantageousin vitroaffinity of compound34for 5-HT1Aand D2receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds32and34revealed antipsychotic-like properties, significantly decreasingd-amphetamine-induced hyperactivity in mice. [ABSTRACT FROM PUBLISHER]

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.

A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a–f, 7a–f and their corresponding alcohols 8a–f were synthesized and evaluated for their affinity towards 5-HT1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (Ki = 2.30 μM) toward 5-HT1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.

[Display omitted] Serotonin (5-hydroxytryptamine) is a small molecule that acts both in the central and peripheral nervous system as a neurotransmitter and a hormone, respectively. Serotonin is synthesized via a multi-stage pathway beginning with l -tryptophan, which is converted by an enzyme called tryptophan hydroxylase into L-5-Hydroxytryptophan. It is well-known for its significance in the control of mood, anxiety, depression, and insomnia as well as in normal human functions such as sleep, sexual activity, and appetite. Thus, for medical chemists and pharmaceutical firms, serotonin is one of the most desirable targets. Among the seven different classes of serotonin receptors, the 5-HT 1A was one of the first discovered serotonin receptors, and the 5-HT 7 was the last addition to the serotonin receptor family. Both the classes were thoroughly examined. 5-HT 1A neurotransmission-related dysfunctions are linked to many psychological conditions such as anxiety, depression, and movement disorders. 5-HT 7 is a member of the cell surface receptor GPCR superfamily and is regulated by the serotonin neurotransmitter. It has been the focus of intensive research efforts since its discovery, which was prompted by its presence in functionally important regions of the brain. The thalamus and hypothalamus have the highest 5-HT 7 receptor densities. They are also found in the hippocampus and cortex at higher densities. Thermoregulation, circadian rhythm, learning and memory, and sleep are all associated with the 5-HT 7 receptor. It is also suspected that this receptor may be involved in the control of mood, indicating that it may be a beneficial target for depression treatment. Several differently structured molecules such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines, and aryloxyalkyl-amines are known to bind to 5-HT 1A and 5-HT 7 receptor sites. In brain serotonin receptors 5-HT 1A and 5-HT 7 are strongly co-expressed in regions involved in depression. However, their functional interaction has not been identified. An overview of the 5-HT 1A and 5-HT 7 receptor ligands belonging to different chemical groups is mentioned in this review. [ABSTRACT FROM AUTHOR]

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 α1 receptors. All compounds with a benzimidazole group had a 5-HT2A/D2 receptors binding ratio characteristic for atypical neuroleptics (>1, pKi 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.

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.

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. .

Arylpiperazines 2 – 11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar p K i of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The synthesis of a series of new n-propyl and n-butyl chain containing 1-arylpiperazine 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.

Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2/5- HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide ( 6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide ( 6b), in experimental autoimmune encephalomyelitis ( EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5- HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM- CSF, TH1 cytokine IFN-γ, TH17 cytokine IL-17, as well as the signature transcription factors of TH1 (T-bet) and TH17 ( RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. [ABSTRACT FROM AUTHOR]

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.

A series of arylpiperazine derivatives of 1,16-diphenyl-19-azahexacyclo-[14.5.1.0.0.0.0]docosa-2,3,5,7,8,9,11,13,14-nonaene-18,20,22-trione and 4,10-diphenyl-1 H,2 H,3 H,5 H-indeno[1,2- f]isoindole-1,3,5-trione was synthesized. The pharmacological profile of compound 4 at the 5-HT receptor was measured by binding assay. The title compounds were tested in cell-based assay against the human immunodeficiency virus type-1. The X-ray crystallographic studies of derivatives 2, 6, 7, 11, 19, and 20 were presented. [ABSTRACT FROM AUTHOR]

Abstract: Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT7 receptors (K i =23.8nM), selectivity over 5-HT1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB=3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain. [Copyright &y& Elsevier]

Serotonin 7 (5-hydroxytryptamine7 or 5-HT) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Here, we report on the structural manipulation of the 5-HT receptor ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine ( 1a) aimed at obtaining 5-HT receptor ligands endowed with good in vitro metabolic stability. A set of N-[3-methoxyphenyl)ethyl-substituted] 1-arylpiperazine, 4-arylpiperidine and 1-aryl-4-aminopiperidine was synthesized and tested in radioligand binding assays at human cloned 5-HT and 5-HT receptors. In vitro metabolic stability of the target compounds was assessed after incubation with rat hepatic S9 microsomal fraction. Among the new compounds, 1-(2-biphenyl)-4-[2-(3-methoxyphenyl)ethyl]piperazine ( 1d) and 4-(2-biphenyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine ( 2d) showed a good compromise between affinity at 5-HT receptor ( K = 7.5 nM and 13 nM, respectively) and in vitro metabolic stability (26 and 65 % recovery of parent compound, respectively) but were poorly selective over 5-HT receptor. [ABSTRACT FROM AUTHOR]

Tandospirone ( I), developed as an anxiolytic drug, is an aryl-piperazine compound that binds to both 5-HT and dopamine D4 receptors. Palladium-catalysed hydroarylation reactions of tandospirone analogues containing an oxygen bridge and 3-(trifluoromethyl)phenyl or 2,3-dichlorophenyl groups were studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted derivatives with potential biological activity. [ABSTRACT FROM AUTHOR]

Abstract: A predictive quantitative structure – activity relationships model of arylpiperazines as high-affinity 5-HT1A receptor ligands was developed using CORAL software (http://www.insilico.eu/CORAL). Simplified molecular input-line entry system (SMILES) was used as representation of the molecular structure of the arylpiperazines. The balance of correlations was used in the Monte Carlo optimization aimed to build up optimal descriptors for one-variable models. The robustness of this model has been tested in four random splits into the sub-training, calibration, and test set. The obtained results reveal good predictive potential of the applied approach: correlation coefficients (r 2) for the test sets of the four random splits are 0.9459, 0.9249, 0.9473 and 0.9362. [Copyright &y& Elsevier]

A series of long-chain arylpiperazines bearing a salicylamide fragment were synthesized, and the target compounds were evaluated for atypical antipsychotic activity in apomorphine-induced climbing behavior (D antagonism) and 5-HTP-induced head twitches (5-HT antagonism) along with catalepsy studies in mice. The physicochemical similarity values of the target compounds with respect to standard drugs, clozapine, ketanserin, and risperidone, were determined using software programs. The test compounds demonstrated good similarity values with respect to the standard drugs. The compounds 3a showed maximum atypical antipsychotic like profile. [ABSTRACT FROM AUTHOR]

Abstract: 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 hD2S receptors were determined in vitro on membranes from stably transfected CHO-hD2S 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. [Copyright &y& Elsevier]

A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a-f, 7a-f and their corresponding alcohols 8a-f were synthesized and evaluated for their affinity towards 5-HT1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan- 1-one (7e) displayed micromolar affinity (Ki = 2.30 μM) toward 5-HT1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides have been synthesized and the target compounds (3a–j) were evaluated for atypical antipsychotic activity in apomorphine induced climbing, 5-HTP induced head twitches behavior and catalepsy studies in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was calculated by using software programs. Among them, compound 3e showed maximum atypical antipsychotic like profile. [Copyright &y& Elsevier]