Agnieszka Zagórska

Synthesis and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione

A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests. The most potent in the series were N-[[4-(3-chlorophenyl)-piperazin-1-yl]-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione (ED50=14.18 mg/kg) and N-[[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl]-3-(3-bromophenyl)-pyrrolidine-2,5-dione (ED50=33.64 mg/kg). Structures of the novel compounds were confirmed by elemental and spectral analyses.

Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3‐Aryl‐pyrrolidine‐2,5‐diones. Part 1

A series of new Mannich bases of N‐[(4‐arylpiperazin‐1‐yl)‐methyl]‐3‐(chlorophenyl)‐pyrrolidine‐2,5‐diones 10–23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES‐test. In this model of seizures, the most active were N‐[{4‐(4‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 16 and N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 17 with ED50 values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10, 14, and 16 were tested in the psychomotor seizure 6‐Hz test from which N‐[{4‐(2‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(2‐chlorophenyl)‐pyrrolidine‐2,5‐dione 10 revealed the highest protection with an ED50 of 78 mg/kg. Compounds 10, 12, and 17 were also tested in the pilocarpine‐induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.

7-3-Chlorophenypiperazinylalkyl derivatives of 8-alkoxy-purine-2, 6-dione as a serotonin receptor ligands with potential antidepressant activity

BACKGROUND The previous study showed that arylpiperazine can condition affinity to α-adrenoceptors, 5-HT1A/5-HT2A receptors and compounds with arylpiperazine had antidepressant-like effect. The aim of this study was to determine the antidepressant-like activity of new arylpiperazines containing novel 8-alkoxy-purine-2,6-dione fragments. METHODS New 3-chloroarylpiperazinylalkyl analogs of 8-alkoxy-purine-2,6-dione and their purine-2,6,8-trione analogs (2-5) were tested for their α1, α2, 5-HT1A,5-HT2A, and 5-HT7 receptor affinities in radioreceptor binding study. Moreover, in search for potential antidepressant properties of these compounds, the forced swim test in mice was conducted. RESULTS Compounds 2 and 3 were potent 5-HT1A receptor ligands with Ki within the range on 12-15 nM. All investigated compounds were found to be highly active 5-HT2A receptor (Ki 15-28 nM) and α1 adrenoceptor (Ki 21-89 nM) ligands. In the forced swim test all the compounds showed a significantly activity in spite of their reducing ability of locomotor activity. The most potent effect was produced by compound 4 and 5, which reduced the immobility time in this test in all used doses. CONCLUSION In our study the most potent antidepressant-like activity was produced by compounds 4 and 5, which are selective for the 5-HT2A and α1 receptors.

Synthesis and Pharmacological Evaluation of Novel Tricyclic[2,1-f]theophylline Derivatives

The multireceptor strategy was implemented to obtain potential antipsychotics and/or antidepressants in a series of long‐chain arylpiperazines bearing a tricyclic theophylline fragment. Their binding profile toward monoaminergic receptors (α1, 5‐HT1A, 5‐HT2A, 5‐HT6, 5‐HT7, D2, D3) was determined as well. The selected compounds 7 and 9 were tested in functional in vivo models and showed, like atypical antipsychotic drugs, presynaptic 5‐HT1A receptor agonistic and postsynaptic 5‐HT1A, 5‐HT2A, and D2 receptor antagonistic activity.

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

Abstract A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4–21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7 and mixed 5-HT1A/5-HT7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.

New Arylpiperazinylalkyl Derivatives of 8‐Alkoxy‐purine‐2,6‐dione and Dihydro[1,3]oxazolo[2,3‐f]purinedione Targeting the Serotonin 5‐HT1A/5‐HT2A/5‐HT7 and Dopamine D2 Receptors

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.

Novel tricyclic[2,1‐f]theophylline derivatives of LCAP with activity in mouse models of affective disorders

The purpose of this study was to investigate the central activity of the two new imidazo[2,1‐f]purine‐2,4‐dione derivatives behaved as presynaptic 5HT1A receptor agonists and postsynaptic 5HT1A, 5HT2A and D2 receptors antagonists. The compounds were examined using animal tests towards antipsychotic, antidepressant‐ and anxiolytic‐like properties and then compared with effects evoked by an atypical antipsychotic drug ziprasidone.

Aminoalkyl Derivatives of 8-Alkoxypurine-2,6-diones: Multifunctional 5-HT1A/5-HT7 Receptor Ligands and PDE Inhibitors with Antidepressant Activity

In the search for potential psychotropic agents, a new series of 3,7‐dimethyl‐ and 1,3‐dimethyl‐8‐alkoxypurine‐2,6‐dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5–16 and 21–32) were synthesized and evaluated for 5‐HT1A/5‐HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1‐(4‐(4‐(2‐hydroxyphenyl)piperazin‐1‐yl)butyl)‐3,7‐dimethyl‐8‐propoxypurine‐2,6‐dione (16) and 7‐(2‐hydroxyphenyl)piperazinylalkyl‐1,3‐dimethyl‐8‐ethoxypurine‐2,6‐diones (31 and 32) as potent dual 5‐HT1A/5‐HT7 receptor ligands with antagonistic activity produced an antidepressant‐like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10−5 M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5‐HT1 and 5‐HT7 receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.

The Lipophilicity Estimation of Selected Dermatological Drugs Using Micellar Electrokinetic Chromatography Method

Lipophilicity is a key physicochemical property which affects pharmacokinetic and pharmacodynamics processes of a drug. This parameter is particularly important for dermatological drugs which should penetrate through the skin barrier. Micellar electrokinetic chromatography (MEKC) method was applied for determination of lipophilicity of salicylic acid and antibiotics commonly used in dermatology. The results of MEKC analysis were compared to lipophilicity coefficients determined by reversed-phase thin-layer chromatography (RM0) and computational (AlogPs, AClogP, logPPallas) methods using principal component analysis (PCA). Thanks to PCA method, a high correlation between the results obtained by both experimental: parameters (logk (MEKC) and RM0 (RP-TLC)) was observed, but the relationship between them and results of the theoretical values were poor.

Serotonin transporter activity of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives in aspect of their acid–base properties

Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid–base properties were evaluated. The dissociation constant (pKa) of compounds 1–22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached.