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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. [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. .

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]

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: 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]

Abstract: The preparation of some lactam (cyclic amide) derivatives bearing various phenylpiperazinylbutyl side chains attached to the amide nitrogen together with their dopamine receptor affinity study is described. The synthesis of the target compounds involved the preparation of the intermediate bromobutyl derivatives of the appropriate lactam followed by N-alkylation of the appropriate phenylpiperazines with these intermediates. Radioligand binding studies at D2–D5 receptor subtypes and a functional calcium assay of the target compounds at D2 and D5 receptor subtypes were performed. All compounds, except 12a and 12b, showed selectivity towards the D2-like receptor subtypes. Selectivity of the indolinone derivatives 11a–d at the D4 receptors was observed. Compound 11b exhibited a remarkable affinity to hD4 receptors with K i value of 0.04±0.02nm and was >43,000-fold selective over the hD2 receptor. In the functional assay, all the active compounds were of antagonistic activity. [Copyright &y& Elsevier]

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