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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 D2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2 ligands. 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 compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice.

To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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]

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]

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]

A series of novel arylpiperazines were synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced climbing behavior (D2 antagonism), 5-HTP induced head twitches (5- HT2A antagonism) and catalepsy studies in albino mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserine and risperidone was assessed by calculating from a set of physiochemical properties using software programs. The test compounds (3a-j) demonstrated good similarity values with respect to the standard drugs. Among them, compound 3d has emerged as an important lead compound showing potential atypical antipsychotic like profile. [ABSTRACT FROM AUTHOR]

Purpose: Arylpiperazines have been recognized as the largest and most diverse class of compounds exerting actions on the central nervous system with strong affinity for serotonin and dopamine receptors. We here report the synthesis of some novel arylpiperazines and their evaluation for possible antipsychotic properties. Methods: The target compounds 2-[4-(aryl substituted) piperazin-1-yl]-N-phenylacetamides (3a-j) were synthesized by first reacting aniline (1) in 2 N sodium hydroxide with chloroacetylchloride in dichloromethane to obtain 2-chloro-N-phenylacetamide (2) and subsequently treating with appropriate phenylpiperazine in acetonitrile in the presence of K2CO3 and KI. All the compounds were characterized by analytical and spectroscopic methods. The compounds were evaluated for antipsychotic activity using three animal models. Results: All the 10 new arylpipeazines showed variable antipsychotic activity with compound 3h being the least effective in the induction of catalepsy. Their effect may involve interaction with 5-HT2A and D2 receptors. Conclusion: A synthetic method and possible antipsychotic effect have been established for 2-[4-(Aryl substituted) piperazin-1-yl]-N-phenylacetamides. [ABSTRACT FROM AUTHOR]

Abstract: Since the discovery of the dopamine D3 receptor, an intensive effort has been directed toward the development of potent and selective ligands in order to elucidate the function and potential therapeutic advantages of targeting D3 receptors. As a part of our efforts, a novel series of substituted benzolactams derivatives was synthesized mostly through palladium-catalyzed reactions. Their affinities on D1–D4 receptors were evaluated and the data led us to highly potent D3 ligands, some of them highly selective for D3 receptor, compared to the related dopamine receptor subtypes. Functional D3 activity assays of the most relevant compounds have been carried out revealing antagonist as well as partial agonist activity. [Copyright &y& Elsevier]

Abstract: An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K2CO3. Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT1A, 5-HT2A and 5-HT2C receptors affinity and allowed to disclose three interesting compounds as 5-HT2C, mixed 5-HT2A/5-HT2C and 5-HT1A/5-HT2C ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profiles. [Copyright &y& Elsevier]

Abstract: A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/or D3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D2 and D3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics. [Copyright &y& Elsevier]

Abstract: Two new series of substituted arylpiperazines with heterocyclic 3-propoxy-benzimidazole or 3-propoxy-benzimidazole-2-thione groups were synthesized and their in vitro binding affinities for the D2, 5-HT1A, 5-HT2A, and α1-adrenergic receptors determined. Among them, only two compounds with phenyl aryl-constituent (8a and 9a) showed 5-HT2A/D2 pK i binding ratios proposed for atypical neuroleptics. As to their behavioral screening on rodents, both compounds exhibited a non-cataleptic action in rats and antagonized d-amphetamine-induced hyperlocomotion in mice, suggesting their possible atypical antipsychotic potency. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]