Design, Synthesis and Pharmacological Evaluation of novel 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

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

Targeting cyclic nucleotide phosphodiesterase 5 (PDE5) in brain: Toward the development of a PET radioligand labeled with fluorine-18

International audienceWith the aim to develop a specific radioligand for imaging the cyclic nucleotide phosphodiesterase 5 (PDE5) in brain by positron emission tomography (PET), seven new fluorinated inhibitors (3-9) were synthesized on the basis of a quinoline core. The inhibitory activity for PDE5 together with a panel of other PDEs was determined in vitro and two derivatives were selected for IC50 value determination. The most promising compound 7 (IC50 = 5.92 nM for PDE5A), containing a 3-fluoroazetidine moiety, was further radiolabeled by aliphatic nucleophilic substitution of two different leaving groups (nosylate and tosylate) using [18F]fluoride. The use of the nosylate precursor and tetra-n-butyl ammonium [18F]fluoride ([18F]TBAF) in 3-methyl-3-pentanol combined with the addition of a small amount of water proved to be the best radiolabeling conditions achieving a RCY of 4.9 ± 1.5% in an automated procedure. Preliminary biological investigations in vitro and in vivo were performed to characterize this new PDE5 radioligand. Metabolism studies of [18F]7 in mice revealed a fast metabolic degradation with the formation of radiometabolites which have been detected in the brain

Efficient Photodynamic Therapy on Human Retinoblastoma Cell Lines

International audiencePhotodynamic therapy (PDT) has shown to be a promising technique to treat various forms of malignant neoplasia. The photodynamic eradication of the tumor cells is achieved by applying a photosensitizer either locally or systemically and following local activation through irradiation of the tumor mass with light of a specific wavelength after a certain time of incubation. Due to preferential accumulation of the photosensitizer in tumor cells, this procedure allows a selective inactivation of the malignant tumor while sparing the surrounding tissue to the greatest extent. These features and requirements make the PDT an attractive therapeutic option for the treatment of retinoblastoma, especially when surgical enucleation is a curative option. This extreme solution is still in use in case of tumours that are resistant to conventional chemotherapy or handled too late due to poor access to medical care in less advanced country. In this study we initially conducted in-vitro investigations of the new cationic water-soluble photo sensitizer tetrahydroporphyrin-tetratosylat (THPTS) regarding its photodynamic effect on human Rb-1 and Y79 retinoblastoma cells. We were able to show, that neither the incubation with THPTS without following illumination, nor the sole illumination showed a considerable effect on the proliferation of the retinoblastoma cells, whereas the incubation with THPTS combined with following illumination led to a maximal cytotoxic effect on the tumor cells. Moreover the phototoxicity was lower in normal primary cells from retinal pigmented epithelium demonstrating a higher phototoxic effect of THPTS in cancer cells than in this normal retinal cell type. The results at hand form an encouraging foundation for further in-vivo studies on the therapeutic potential of this promising photosensitizer for the eyeball and vision preserving as well as potentially curative therapy of retinoblastoma

Structure-activity relationship, docking analysis and ADME properties of newly designed, potent serotonin 5HT1a receptor ligands

Serotonin 5HT1a receptors belongs to a class G-protein coupled receptors and it is widely recognized as one of the targets for treating neurological disorders such depression and schizophrenia. N-arylpiperazine structural motif is present in many compounds with pronounced 5HT1a activity including recently approved aripiprazole for the treatment of the major depressive disorder

Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1- yl)ethyl]phenyl} arylamides

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