Quantitative structure-affinity relationship of 5-HT1A receptor ligands by the classification tree method

The influence of molecular structure of 346 ligands on their affinity for 5-HT_1A receptors was investigated. It was shown that the effectiveness of the proposed novel approach for interpretation of decision tree models compared favourably with the PLS method. In the context of the proposed approach, molecular fragments and their values of the relative influence on the affinity for 5-HT_1A receptors were defined.     

Synthesis of GR 125487, a selective 5-HT4 receptor antagonist

The 5-HT₄ receptor (5-HT₄R) agonists are important in treating gastrointestinal motility disorders. Their role is currently being evaluated for the treatment of cognitive and mood disorders. A selective 5-HT₄R antagonist GR 125487 is used in many biological assays to cross confirm the 5-HT₄R agonist’s activity. A practical synthesis of GR 125487 is developed so as to have it in desired quantities. The synthesis consists of seven steps starting from commercially available methyl 5-fluoroindole 3-carboxylate. The GR 125487 thus synthesized was used in blocking the activity of 5-HT₄R agonist compound in animal models of cognition.     

Synthesis of hexahydro[2]benzopyrano[4,3-c]pyridines as serotonin 5-HT2C receptor agonists via intramolecular hetero Diels-Alder reactions

Hexahydro[2]benzopyrano[4,3-c]pyridines were synthesized by an intramolecular hetero Diels-Alder reaction. The reaction was applicable to a range of substrates and the products could be easily converted into serotonin 5-HT_2C receptor agonists.     

Synthesis of hexahydro[2]benzopyrano[3,4-c]pyrroles as serotonin 5-HT2C receptor agonists via intramolecular hetero Diels-Alder reactions

[2]Benzopyrano[3,4-c]pyrroles were synthesized via an intramolecular hetero Diels-Alder reaction. The reaction was applicable to a wide range of substrates and the products could be easily converted into serotonin 5-HT_2C receptor agonists.     

Synthesis,Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT_1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT_1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.     

A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor

A homology-based model of the 5-HT_2A receptor was produced utilizing an activated form of the bovine rhodopsin (Rh) crystal structure [1,2]. In silico activation of the Rh structure was accomplished by isomerization of the 11-cis-retinal (1) chromophore, followed by constrained molecular dynamics to relax the resultant high energy structure. The activated form of Rh was then used as a structural template for development of a human 5-HT_2A receptor model. Both the 5-HT_2A receptor and Rh are members of the G-protein coupled receptor (GPCR) super-family. The resulting homology model of the receptor was then used for docking studies of compounds representing a cross-section of structural classes that activate the 5-HT_2A receptor, including ergolines, tryptamines, and amphetamines. The ligand/receptor complexes that ensued were refined and the final binding orientations were observed to be compatible with much of the data acquired through both diversified ligand design and site directed mutagenesis.     

Design,Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α₂-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT₇ receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α₂-adrenoceptors and 5-HT₇ receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α_2A/5-HT₇ receptor antagonist and displayed moderate-to-high selectivity over α₁-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.     

1-[2-（2-Methoxyphenylthio） benzyl]-4-arylpiperazines derivatives： Synthesis and evaluation for dual 5-HT1A/SSRI activities

A series of 1-[2-（2-methoxyphenylthio） benzyl]-4-arylpiperazines derivatives was designed and synthesized based on 5-HT1A/ SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

1-（N-（2-（2-Methoxyphenylthio）benzyl）-N-methylamino-3-aryloxypropan-2-ols： Synthesis and evaluation for dual 5-HT1A/SSRI activities

A series of 1-（N-（2-（2-methoxyphenylthio）benzyl）-N-methylamino-3-aryloxypropan-2-ols derivatives were designed and synthesized based on 5-HT1A/SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/ 5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

Design and Synthesis of Arylpiperazine Serotonergic/Dopaminergic Ligands with Neuroprotective Properties

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT_1A, 5-HT_2A, 5-HT₇ receptor, and dopamine D₂ receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood–brain barrier. We identified compound 12a that combines an affinity profile compatible with antipsychotic activity (5-HT_1A K_i = 41.5 nM, 5-HT_2A K_i = 315 nM, 5-HT₇ K_i = 42.5 nM, D₂ K_i = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT_1A K_i = 23.9 nM, 5-HT_2A K_i = 39.4 nM, 5-HT₇ K_i = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound 9b, which might be suitable for studies in vivo.     

Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as serotonin 5-HT4 receptor agonists

A series of N-azabicycloalkyl-1-alkyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT4 receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT4 receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1 oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, ED50 = 36.3 nMi), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10 microM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).     

Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists

We report a structure-affinity analysis of an important element in the pharmacophore model for the recognition of 5-HT4 receptor antagonists: the voluminous substituent attached to the basic nitrogen of the ligand. We have designed, synthesized and pharmacologically evaluated a series of benzimidazole derivatives 1 containing a common molecular skeleton formed by N-[(4-piperidyl)methyl]-6-chlorobenzimidazole-4-carboxamide and four different substituents (R = butyl, 2-[(methylsulfonyl)amino]ethyl, 5-[(phenylacetyl)amino]pentyl, and 5-[(benzylsulfonyl)amino]pentyl). These compounds possess binding affinities in the nM range (Ki = 0.11-1.50 nM). Moreover, a ligand that contains a hydrogen atom attached to the basic nitrogen (R = H; Ki = 150 nM) is used as a control for structure-affinity relationships.     

Determination of fumonisins B1 and B2 in Portuguese maize and maize-based samples by HPLC with fluorescence detection

Fumonisins B₁ (FB₁) and fumonisin B₂ (FB₂) are the main members of a family of mycotoxins produced by Fusarium verticillioides, Fusarium proliferatum, and other fungi species of the section Liseola. The present work shows the results of comparative studies using two different procedures for the analysis of fumonisins in maize and maize-based samples. The studied analytical methods involve extraction with methanol/water, dilution with PBS, and clean-up through immunoaffinity columns. Two reagents (o-phthaldialdehyde and naphthalene-2,3-dicarboxaldehyde) were studied for formation of fluorescent derivatives. The separation and identification were carried out by high-performance liquid chromatography with fluorescence detection. The optimized method for analysis of fumonisins in maize involved extraction with methanol/water (80:20), clean-up with an immunoaffinity column, and derivatization with naphthalene-2,3-dicarboxaldehyde (NDA). The limit of detection was 20 μg kg⁻¹ for FB₁ and 15 μg kg⁻¹ for FB₂. Recoveries of FB₁ and FB₂ ranged from 79% to 99.6% for maize fortified at 150 μg kg⁻¹ and 200 μg kg⁻¹, respectively, with within-day RSDs of 3.0 and 2.7%. The proposed method was applied to 31 samples, and the presence of fumonisins was found in 14 samples at concentrations ranging from 113 to 2,026 μg kg⁻¹. The estimated daily intake of fumonisins was 0.14 μg kg⁻¹ body weight per day.     

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT_1A, 5-HT_2A, 5-HT₆, and D₂ receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D₂ receptor antagonists with additional 5-HT₆R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT₆R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT₆R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D₂R antagonist function combined with 5-HT₆R agonism, and mixed D₂/5-HT₆R antagonists in murine models of psychosis.     

Arylpiperazine derivatives of diphenylsulfide:Synthesis and evaluation for dual 5-HT1A/SSRI activities

The design, synthesis and biological evaluation of a novel series of arylpiperazine derivatives of diphenylsulfide with dual 5- HT1A/SSRI activities are reported. The target compounds exhibit low to moderate 5-HT transporter affinity and moderate to high 5- HT1A affinity, Compound 13a shows moderate dual activities and is a promising lead compound for further structure-activity relationships studies.     

Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.     

One-Pot,Facile, Highly Efficient,and Green Synthesis of Acridinedione Derivatives Using Vitamin B1

An efficient methodology for the synthesis of acridinedione derivatives 4a–o has been achieved by one-pot, multicomponent condensation of dimedone 1, various amines 2a–d, and substitute aromatic aldehydes 3a–k, in the presence of the easily available, inexpensive, and nontoxic catalyst vitamin B₁ (VB₁) as a versatile biodegradable. Synthesis of acridine-type compounds was performed in good yields in water as green solvent. Its high-yield efficiency; clean, ecofriendly, simple workup procedure; and easy purification are regarded as the main advantages of this method besides its green solvent. The synthesized compounds are characterized using spectroscopic analyses (FTIR, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry) techniques.     

Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT₇R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT₇R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT₇R/G₁₂ signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT₇R could be a potential therapeutic target for the treatment of NDDs.     

A comparative QSAR analysis and molecular docking studies of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors

Depression is a critical mood disorder that affects millions of patients. Available therapeutic antidepressant agents are associated with several undesirable side effects. Recently, it has been shown that Neurokinin 1 receptor (NK₁R) antagonists can potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs). In this study, a series of phenyl piperidine derivatives as potent dual NK₁R antagonists/serotonin transporter (SERT) inhibitors were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and NK₁R antagonism/SERT inhibitory of these compounds. The best multiple linear regression equation was obtained from GA-PLS and MLR for NK₁R and SERT, respectively. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed for both targets. Molecular docking studies of these compounds on both targets were also conducted and encouraging results were acquired. There was a good correlation between QSAR and docking results. The results obtained from validated docking studies indicate that the important amino acids inside the active site of the cavity that are responsible for essential interactions are Glu33, Asp395 and Arg26 for SERT and Ala30, Lys7, Asp31, Phe5 and Tyr82 for NK₁R receptors.