Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model.

The newly emerged pathogen, Candida auris, presents a serious threat to public health worldwide. This multidrug-resistant yeast often colonizes and persists on the skin of patients, can easily spread from person to person, and can cause life-threatening systemic infections. New antifungal therapies are therefore urgently needed to limit and control both superficial and systemic C. auris infections. In this study, we designed a novel antifungal agent, PQA-Az-13, that contains a combination of indazole, pyrrolidine, and arylpiperazine scaffolds substituted with a trifluoromethyl moiety. PQA-Az-13 demonstrated antifungal activity against biofilms of a set of 10 different C. auris clinical isolates, representing all four geographical clades distinguished within this species. This compound showed strong activity, with MIC values between 0.67 and 1.25 µg/mL. Cellular proteomics indicated that PQA-Az-13 partially or completely inhibited numerous enzymatic proteins in C. auris biofilms, particularly those involved in both amino acid biosynthesis and metabolism processes, as well as in general energy-producing processes. Due to its hydrophobic nature and limited aqueous solubility, PQA-Az-13 was encapsulated in cationic liposomes composed of soybean phosphatidylcholine (SPC), 1,2-dioleoyloxy-3-trimethylammonium-propane chloride (DOTAP), and N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt (DSPE-PEG 2000), and characterized by biophysical and spectral techniques. These PQA-Az-13-loaded liposomes displayed a mean size of 76.4 nm, a positive charge of +45.0 mV, a high encapsulation efficiency of 97.2%, excellent stability, and no toxicity to normal human dermal fibroblasts. PQA-Az-13 liposomes demonstrated enhanced antifungal activity levels against both C. auris in in vitro biofilms and ex vivo skin colonization models. These initial results suggest that molecules like PQA-Az-13 warrant further study and development.

Synthesis, computational simulations and biological evaluation of new dual 5HT1A/5HT7 receptor ligands based on purine-2,6-dione scaffold.

The new dual 5HT1A/5HT7 receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HT1AR and 5HT7R, and was the most potent antagonist of 5-HT1AR (Kb = 0.26 ± 0.1 nM) which activity can be to reference compound NAN-190 (Kb = 0.26 ± 0.1 nM). The experimentally established physicochemical parameters of compound 11 showed that compound, as slightly ionized in the blood, could penetrate the blood-brain barrier. A molecular docking study showed that the fluorine substitution introduces additional stabilization effects on binding to 5HT1A/5HT7Rs. In animal assays of depression and anxiety, compound 11 revealed activity in terms of dosage compared to marketed psychotropics such as fluoxetine, citalopram, and sertraline.

The Antidepressant-like Activity, Effects on Recognition Memory Deficits, Bioavailability, and Safety after Chronic Administration of New Dual-Acting Small Compounds Targeting Neuropsychiatric Symptoms in Dementia.

This study aimed to extend the body of preclinical research on prototype dual-acting compounds combining the pharmacophores relevant for inhibiting cyclic nucleotide phosphodiesterase 10 (PDE10A) and serotonin 5-HT1A/5-HT7 receptor (5-HT1AR/5-HT7R) activity into a single chemical entity (compounds PQA-AZ4 and PQA-AZ6). After i.v. administration of PQA-AZ4 and PQA-AZ6 to rats, the brain to plasma ratio was 0.9 and 8.60, respectively. After i.g. administration, the brain to plasma ratio was 5.7 and 5.3, respectively. An antidepressant-like effect was observed for PQA-AZ6 in the forced swim test, after chronic 21-day treatment via i.p. administration with 1 mg/kg/day. Both compounds revealed an increased level of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus and prefrontal cortex. Moreover, PQA-AZ4 and PQA-AZ6 completely reversed (+)-MK801-induced memory disturbances comparable with the potent PDE10 inhibitor, compound PQ-10. In the safety profile that included measurements of plasma glucose, triglyceride, and total cholesterol concentration, liver enzyme activity, the total antioxidant activity of serum, together with weight gain, compounds exhibited no significant activity. However, the studied compounds had different effects on human normal fibroblast cells as revealed in in vitro assay. The pharmacokinetic and biochemical results support the notion that these novel dual-acting compounds might offer a promising therapeutic tool in CNS-related disorders.

Estimation of the lipophilicity of purine-2,6-dione-based TRPA1 antagonists and PDE4/7 inhibitors with analgesic activity.

Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (RM0) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the Kruskal-Wallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity.

Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-ß-Carbolines.

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

A Label-Free Cellular Proteomics Approach to Decipher the Antifungal Action of DiMIQ, a Potent Indolo[2,3-b]Quinoline Agent, against Candida albicans Biofilms.

Candida albicans forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) was evaluated against C. albicans biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, Cryptolepis sanguinolenta. Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited C. albicans biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits C. albicans biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated Candida infections.

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer's Disease Therapy.

Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3ß), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

Synthesis and pharmacological evaluation of novel N-Mannich bases derived from 5,5-diphenyl and 5,5-di(propan-2-yl)imidazolidine-2,4-dione core.

The aim of this study was to design and synthesize two series of N-Mannich bases with imidazolidine-2,4-dione core as a potential anticonvulsant with reduced toxicity and broad antiseizure activity. Preliminary screening revealed that the majority of synthesized compounds were effective in the maximal electroshock seizure (MES) and/or subcutaneous pentylenetetrazole (scPTZ) test. The most active in vivo compound, 18 (3-((4-methylpiperazin-1-yl)methyl)-5,5-diphenylimidazolidine-2,4-dione), exhibited an ED50 value comparable to that of phenytoin in the MES test (38.5 mg/kg vs 28.1 mg/kg), and more importantly, it showed four times higher potency than phenytoin in the 6 Hz test (12.2 mg/kg vs > 60 mg/kg). Additionally, 18 exhibited antiallodynic properties in the von Frey test in neuropathic (oxaliplatin-treated) mice. Compound 18 also demonstrated a broader spectrum of anticonvulsant activity than phenytoin and showed statistically significant antinociceptive properties in selected models of chronic pain.

Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability.

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2-1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.

Determination of ligand efficiency indices in a group of 7H-purine-2,6-dione derivatives with psychotropic activity using micellar electrokinetic chromatography.

Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules and lipophilic properties. Lipophilicity of drug candidate can affect both the pharmacokinetic and pharmacodynamics properties, in particular, the ability of a molecule to cross the cell membrane. Among the new methods for determination of the lipophilicity of compounds, micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of the lipophilicity of 24 derivatives of 8-alkoxy-7H-purine-2,6-dione, designed and synthesized as potential antidepressant/anxiolytic and antipsychotic agents. The results of experimental method were compared with calculated in silico parameters (AlogPs and milogP by Virtual Computational Laboratory website, log PPallas by Pallas 3.1, Mlog P by Marvin, log PChemS by ChemSketch, log PChemDraw by ChemBioUltra) using Principal Component Analysis (PCA) method. Finally, using estimated log P values for selected compounds ligand - lipophilicity efficiency (LLE), per cent efficiency index (PEI), and binding efficiency index (BEI) parameters were calculated. Applied MEKC procedure could be used for selection of potential lead structure in a group of 7H-purine-2,6-dione derivatives.

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents.

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 µM and 20.5 µM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.

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.

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.

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.

RECEPTOR AFFINITY AND PHOSPHODIESTERASES 4B AND 10A ACTIVITY OF OCTAHYDRO- AND 6,7-DIMETHOXY-3,4-DIHYDRO- ISOQUINOLIN-2(1H)-YL-ALKYL DERIVATIVES OF IMIDAZO- AND PYRIMIDINO[2,1-f]PURINES.

A series of octahydro- and 6,7-dimethoxy-3,4-dihydro- isoquinolin-2(1H)-yl-alkyl derivatives of imidazo- and pyrimidino[2,1-f]purines were synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT(1A), 5-HT(6), 5-HT(7), and dopamine D2 receptors and inhibitory potencies for phosphodiesterases - PDE4B1 and PDE10A. The structure-activity relationships allowed to determine the structural features responsible for receptor and enzyme activity. Compound 5 (8-(4-(6,7-dimethoxy-3,4-dihydroiso- quinolin-2(1H)butyl)1,3-dimethyl-H-imidazo[2,1-f]purine-2,4(3H,8H)-dione) could be regarded as promising structure for further modification and detailed mechanistic study for obtained hybrid ligands.

NEW SPIROHYDANTOIN DERIVATIVES - SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING STUDY.

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1'-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HTIA, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic ox, receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT 1A/7, was also analyzed in computational stud- ies. Moreover, two highly selective (9 and HI) 5-HT2A receptor antagonists were obtained.

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.

REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY STUDY OF LIPOPHILICITY OF IMIDAZO[2,1-F]THEOPHYLLINE DERIVATIVES.

The present study is a part of our physicochemical and pharmacological studies in a group of tricyclic theophylline derivatives. The investigated compounds exhibit different pharmacological profiles in comparison to theophylline and have been tested as potential antidepressant and/or antipsychotic agents. The differences in pharmacological action between theophylline and their tricyclic derivatives can be explained by their various physicochemical properties, especially lipophilicity. The chromatographic behavior of twenty three derivatives of imidazo[2,1-ƒ]theophylline was investigated, using reversed-phase high performance liquid chromatography (RP-HPLC) method. Moreover, partition coefficients and selected pharmacokinetic parameters were calculated computationally. Principal component analysis (PCA) method was used to establish the relationship between obtained experimental and computational parameters.

Reversed-phase TLC study of some long chain arylpiperazine of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives.

The chromatographic parameters of arylpiperazinylpropyl derivatives of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione were investigated using reversed-phase thin layer chromatography method. The results revealed that R(M0) of investigated compounds depended on substituent in arylpiperazinyl fragment as well as on a nature of (cycloalkyl)aromatic ring at 5 position of imidazolidine-2,4-dione and at 7 position of imidazo[2,1-f]theophylline. The R(M0) parameters were compared with computationally calculated partition coefficients values by principal component analysis (PCA). To verify the influence of lipophilic parameter of investigated compounds on their biological activity the statistical analysis of Mann-Whitney was performed.

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-HT(1A), 5-HT(2A), 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-HT(1A) receptor agonistic and postsynaptic 5-HT(1A), 5-HT(2A), and D2 receptor antagonistic activity.