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Abstract

Imidazoline receptor ligands are a numerous family of biologically active compounds known to produce central hypotensive effect by interaction with both α2-adrenoreceptors (α2-AR) and imidazoline receptors (IRs). Recent hypotheses connect those ligands with several neurological disorders. Therefore some IRs ligands are examined as novel centrally acting antihypertensives and drug candidates for treatment of various neurological diseases. Effective Blood-Brain Barrier (BBB) permeability (Pe) of 18 IRs/α-ARs ligands and 22 Central Nervous System (CNS) drugs was experimentally determined using Parallel Artificial Membrane Permeability Assay (PAMPA) and studied by the Quantitative-Structure-Permeability Relationship (QSPR) methodology. The dominant molecules/cations species of compounds have been calculated at pH = 7.4. The analyzed ligands were optimized using Density Functional Theory (B3LYP/6-31G(d,p)) included in ChemBio3D Ultra 13.0 program and molecule descriptors for optimized compounds were calculated using ChemBio3D Ultra 13.0, Dragon 6.0 and ADMET predictor 6.5 software. Effective permeability of compounds was used as dependent variable (Y), while calculated molecular parametres were used as independent variables (X) in the QSPR study. SIMCA P+ 12.0 was used for Partial Least Square (PLS) analysis, while the stepwise Multiple Linear Regression (MLR) and Artificial Neural Networks (ANN) modeling were performed using STASTICA Neural Networks 4.0. Predictive potential of the formed models was confirmed by Leave-One-Out Cross- and external-validation and the most reliable models were selected. The descriptors that are important for model building are identified as well as their influence on BBB permeability. Results of the QSPR studies could be used as time and cost efficient screening tools for evaluation of BBB permeation of novel α-adrenergic/imidazoline receptor ligands, as promising drug candidates for treatment of hypertension or neurological diseases.

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... However, since we only evaluated the leave one environment out crossvalidation scheme, our assertions are valid only for this context. However, other authors (Campbell and Ntobedzi, 2007;Bergström et al., 2012;Vucicevic et al., 2015;Zhang et al., 2015;Kouskoura et al., 2019) have evaluated the prediction accuracy of the PLS methodology with conventional strategies of cross-validation (k-fold cross-validations, stratified-k-fold cross-validations, etc.) and there is also empirical evidence that the PLS regression method produces very competitive predictions. ...
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In plant breeding, the need to improve the prediction of future seasons or new locations and/or environments, also denoted as "leave one environment out," is of paramount importance to increase the genetic gain in breeding programs and contribute to food and nutrition security worldwide. Genomic selection (GS) has the potential to increase the accuracy of future seasons or new locations because it is a predictive methodology. However, most statistical machine learning methods used for the task of predicting a new environment or season struggle to produce moderate or high prediction accuracies. For this reason, in this study we explore the use of the partial least squares (PLS) regression methodology for this specific task, and we benchmark its performance with the Bayesian Genomic Best Linear Unbiased Predictor (GBLUP) method. The benchmarking process was done with 14 real datasets. We found that in all datasets the PLS method outperformed the popular GBLUP method by margins between 0% (in the Indica data) and 228.28% (in the Disease data) across traits, environments, and types of predictors. Our results show great empirical evidence of the power of the PLS methodology for the prediction of future seasons or new environments.
... Due to the neuroprotective function of the I2 receptor, ligands have been designed to have high affinity for I2IRs and low for α2 receptors, including BU224, LSL60101 and CR4056 [32,33] (Figure 1B), which have also been shown to readily cross the BBB [34]. The pharmacology of I2IRs is more complex than that of most conventional receptors. ...
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Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-NOur results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.
... Having early information on pharmacokinetic properties, metabolism and potential toxicity is crucial in order to avoid the risk of late-stage failures, as well as to guide the lead optimisation by increasing its drug-like properties. Moreover, ADMET data may be analysed by building predictive QSAR models to search for correlations between the activity and a wide variety of ADMET descriptors (58)(59)(60). Currently, there are many commercially available as well as free-to-use programmes that can be used for in silico ADMET profiling, such as: Swiss-ADME (61), ADMET Predictor (62), Schrodinger-QikProp (63) and many others (58,59). ...
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Drug discovery and development is a very challenging, expensive and time-consuming process. Impressive technological advances in computer sciences and molecular biology have made it possible to use computer-aided drug design (CADD) methods in various stages of the drug discovery and development pipeline. Nowadays, CADD presents an efficacious and indispensable tool, widely used in medicinal chemistry, to lead rational drug design and synthesis of novel compounds. In this article, an overview of commonly used CADD approaches from hit identification to lead optimization was presented. Moreover, different aspects of design of multitarget ligands for neuropsychiatric and anti-inflammatory diseases were summarized. Apparently, designing multi-target directed ligands for treatment of various complex diseases may offer better efficacy, and fewer side effects. Antipsychotics that act through aminergic G protein-coupled receptors (GPCRs), especially Dopamine D2 and serotonin 5-HT2A receptors, are the best option for treatment of various symptoms associated with neuropsychiatric disorders. Furthermore, multi-target directed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors are also a successful approach to aid the discovery of new anti-inflammatory drugs with fewer side effects. Overall, employing CADD approaches in the process of rational drug design provides a great opportunity for future development, allowing rapid identification of compounds with the optimal polypharmacological profile.
... Sci. 2020,21, 2534 ...
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As the number of central nervous system (CNS) drug candidates is constantly growing, there is a strong need for precise a priori prediction of whether an administered compound is able to cross the blood–brain barrier (BBB). The aim of this study was to evaluate the ability to cross the BBB of triterpenoid saponins occurring in Astragalus mongholicus roots. The research was carried out using in silico methods combined with postmortem studies on the brain tissues of mice treated with isolated astragaloside IV (AIV). Firstly, to estimate the ability to cross the BBB by the tested saponins, new quantitative structure–activity relationship (QSAR) models were established. The reliability and predictability of the model based on the values of the blood–brain barrier penetration descriptor (logBB), the difference between the n-octanol/water and cyclohexane/water logP (∆logP), the logarithm of n-octanol/water partition coefficient (logPow), and the excess molar refraction (E) were both confirmed using the applicability domain (AD). The critical leverage value h* was found to be 0.128. The relationships between the standardized residuals and the leverages were investigated here. The application of an in vitro acetylcholinesterase-inhibition test showed that AIV can be recognized as the strongest inhibitor among the tested compounds. Therefore, it was isolated for the postmortem studies on brain tissues and blood using semi-preparative HPLC with the mobile phase composed of water, methanol, and ethyl acetate (1.7:2.1:16.2 v/v/v). The results of the postmortem studies on the brain tissues show a regular dependence of the final concentration of AIV in the analyzed brain samples of animals treated with 12.5 and 25 mg/kg b.w. of AIV (0.00012299 and 0.0002306 mg, respectively, per one brain). Moreover, the AIV logBB value was experimentally determined and found to be equal to 0.49 ± 0.03.
... Generally, PLS is a rapid and effective method for developing robust and reliable QSAR models. It has been widely used for the design of plenty of predictive patterns, such as for the placental-barrier permeability [18], blood-brain-barrier permeability from simulated chromatographic conditions [19], central nervous system (CNS) drug exposure [20], blood-brain barrier permeation of α-adrenergic and imidazoline receptor ligands using the parallel artificial membrane permeability assay (PAMPA) technique [21]. Additionally, PLS tool was used to discover potent Wee1 inhibitors [22], to evaluate 2-cyano-pyrimidine analogs as cathepsin-K inhibitors [23] and also to characterize the performance of dry powder inhalers [24]. ...
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One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs’ behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a reliable predictive tool. The present study attempts to decode the permeability by correlating the apparent permeability coefficient (Papp) of 33 steroids with their properties (physicochemical and structural). The Papp of the molecules was determined by in vitro experiments and the results were plotted as Y variable on a Partial Least Squares (PLS) model, while 37 pharmacokinetic and structural properties were used as X descriptors. The developed model was subjected to internal validation and it tends to be robust with good predictive potential (R2Y = 0.902, RMSEE = 0.00265379, Q2Y = 0.722, RMSEP = 0.0077). Based on the results specific properties (logS, logP, logD, PSA and VDss) were proved to be more important than others in terms of drugs Papp. The models can be utilized to predict the permeability of a new candidate drug avoiding needless animal experiments, as well as time and material consuming experiments.
... In the past, the comparative molecular field analysis (CoMFA) was widely applied, but the nonlinear pattern recognition ability of ANNs was recognized to be better suited in developing QSARs (K€ ovesdi et al., 1999). ANN QSPR models were also found to be the most statistically relevant when compared to PLS and MLR (Vucicevic, Nikolic, Dobri ci c, & Agbaba, 2015). ...
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Aromatherapy with essential oils (EOs) has been linked to improvement of cognitive function in patients with dementia. In order to act systemically, active EO components must be absorbed through the skin, enter the systemic circulation, and cross the blood brain barrier (BBB). Thus, the aim of this work was to develop quantitative structure activity relationships (QSARs), to predict skin and blood barrier penetrative abilities of 119 terpenoids from EOs used in aromatherapy. The first model was based on experimentally measured skin permeability for 162 molecules, and the second model on BBB permeability for 138 molecules. Each molecule was encoded with 63 calculated molecular descriptors and an artificial neural network was used to correlate molecular descriptors to permeabilities. Developed QSAR models confirm that EOs components penetrate through the skin and across the BBB. Some well-known descriptors, such as log P (lipophilicity), molecular size and shape, dominated the QSAR model for BBB permeability. Compounds with the highest predicted BBB penetration were hydrocarbon terpenes with the smallest molecular size and highest lipophilicity. Thus, molecular size is a limiting factor for penetration. Compounds with the highest skin permeability have slightly higher molecular size, high lipophilicity and low polarity. Our work shows that a major disadvantage of novel multitarget compounds developed for the treatment of Alzheimer’s disease is the size of molecules, which cause problems in their delivery to the brain. Therefore, there is a need for smaller compounds, which possess more desirable physicochemical properties and pharmacokinetics, in addition to targeted biological effects. Communicated by Ramaswamy H. Sarma
... Prediction of BBB permeability Quantitative structurepermeability relationship (QSPR) methodology [66] PAMPA Predicting PAMPA BBB power for permeation assay HPLC-UV [67] PAMPA and porcine brain endothelial cell models Assessment of the blood-brain barrier permeability HPLC-UV, LC-MS/MS [39,68] ECV304 and bEnd3 cell layers Characterization of suitable cell lines that mimics the in vivo BBB permeability conditions LC-MS/MS, immunofluorescence microscopy [69,70] www.drugdiscoverytoday.com 1171 Mdr1a/1b À/À and wild-type mice Plasma and brain tissue ...
... New ligands enable detection and imaging studies for distribution and occupancy of I 2 sites (Tyacke et al., 2012, Kealey et al., 2013, Keller and Garcia-Sevilla, 2015. Further development will be aided by computational methods, both for structure-function relationships and for drug-like properties to ensure brain permeation (Moraes and de Azevedo, 2012, Nikolic and Agbaba, 2012, Vucicevic et al., 2015. With better understanding of the pharmacology of I 2 sites, behavioral studies are also now appearing (Qiu et al., 2014, Qiu et al., 2015. ...
... New ligands enable detection and imaging studies for distribution and occupancy of I 2 sites (Tyacke et al., 2012;Kealey et al., 2013;Keller and Garcia-Sevilla, 2015). Further development will be aided by computational methods, both for structure-function relationships and for drug-like properties to ensure brain permeation (Moraes and De Azevedo, 2012;Nikolic and Agbaba, 2012;Vucicevic et al., 2015). With better understanding of the pharmacology of I 2 sites, behavioral studies are also now appearing (Qiu et al., 2014(Qiu et al., , 2015. ...
Article
Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the effect of alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I 2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.
... New ligands enable detection and imaging studies for distribution and occupancy of I 2 sites (Tyacke et al., 2012, Kealey et al., 2013, Keller and Garcia-Sevilla, 2015. Further development will be aided by computational methods, both for structure-function relationships and for drug-like properties to ensure brain permeation (Moraes and de Azevedo, 2012, Nikolic and Agbaba, 2012, Vucicevic et al., 2015. With better understanding of the pharmacology of I 2 sites, behavioral studies are also now appearing (Qiu et al., 2014, Qiu et al., 2015. ...
Article
Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.
... Other approaches aimed at gaining preliminary permeability data in vitro include the artificial membrane-based PAMPA (Parallel Artificial Membrane Permeability Assay), discussed in more detail in the following chapter in the context of nonanimal intestinal models (Avdeef et al., 2007(Avdeef et al., , 2008Flaten et al., 2006bFlaten et al., , 2007Kansy et al., 1998Kansy et al., , 2004, as well as Strat-M™, available from Merck. The first commercially available PAMPA for performing penetration studies is the skin-PAMPA, as supplied by Pion Inc. Skin-PAMPA consists of a complete test system, including UV reader, as well as required technical support and is already in use for determination of temperature and protein-binding effects, for evaluation of new compounds and for predictive approaches studying quantitative structurepermeability relationships (Akamatsu et al., 2009;Bujard et al., 2014;Dobricic et al., 2014;Markovic et al., 2012;Vizseralek et al., 2014;Vucicevic et al., 2015). In contrast, the skin-mimicking artificial membrane setup Strat-M™ (Merck Millipore, USA) is composed of multiple layers of polyether sulfone, which is compatible with Franz chamber setups. ...
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Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
... The role of membrane retention (MR) is still a controversial issue (Avdeef, 2012b). In general, studies focused on the scope of the PAMPA mechanism avoided to discuss the MR results of permeability measurements (Mensch et al., 2010;Vucicevic et al., 2015). We suppose that MR might refer to lipophilicity; however no strong functional relation was found between MR and logP or logD 7.4 , a slight trend only. ...
Article
Due to its robustness and versatility, several variations of the blood-brain barrier specific parallel artificial membrane permeability assay (PAMPA-BBB) have been reported in the central nervous system (CNS) drug discovery practice. In this study, the impact of the main assay parameters on the predictive power of PAMPA-BBB was thoroughly investigated with 27, passively BBB-transported drug molecules with in vivo logBB data. The single and combined effects of the following variables were systematically studied and optimized: incubation time and temperature (4 vs. 18h, RT vs. 37°C), type of the read-out (UV-reader vs. HPLC), solvent composition (n-dodecane/n-hexane), lipid concentration (0-10w/v% PBLE), cholesterol content (0-1.66w/v%), and thickness of the lipid membrane, and the DMSO cosolvent content (5-20v/v%), respectively. Based on our results, solvent-driven and lipid-driven mechanisms of diffusion were identified in different assay conditions. Moreover, the analysis of membrane retention (MR%; the mole fraction of solute "lost" to the membrane) data obtained at various membrane compositions (volume of solvent and concentration of phospholipids) revealed the compound-specific nature of this parameter. The optimized conditions for the PAMPA-BBB were the following: 4h incubation at 37°C, detection by HPLC-DAD, iso-pH conditions (pH=7.4) with 5v/v% DMSO content in buffer solutions, and PBLE (10w/v%; without cholesterol) as membrane dissolved in the mixture of n-hexane: n-dodecane 3:1.
... PLS cannot only avoid collinearity or auto-correlation problems but also address the puzzles in ANN and GA. Therefore, PLS as a rapid and effective method was widely used to develop robust and predictable QSAR models [36][37][38][39]. ...
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Assessing the human placental barrier permeability of drugs is very important to guarantee drug safety during pregnancy. Quantitative structure-activity relationship (QSAR) method was used as an effective assessing tool for the placental transfer study of drugs, while in vitro human placental perfusion is the most widely used method. In this study, the partial least squares (PLS) variable selection and modeling procedure was used to pick out optimal descriptors from a pool of 620 descriptors of 65 compounds and to simultaneously develop a QSAR model between the descriptors and the placental barrier permeability expressed by the clearance indices (CI). The model was subjected to internal validation by cross-validation and y-randomization and to external validation by predicting CI values of 19 compounds. It was shown that the model developed is robust and has a good predictive potential (r2=0.9064, RMSE=0.09, q2=0.7323, rp2=0.7656, RMSP=0.14). The mechanistic interpretation of the final model was given by the high variable importance in projection values of descriptors. Using PLS procedure, we can rapidly and effectively select optimal descriptors and thus construct a model with good stability and predictability. This analysis can provide an effective tool for the high-throughput screening of the placental barrier permeability of drugs.
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This study observed the cutaneous analgesic effect of adrenergic agonists when combined with lidocaine. We aimed at the usefulness of 4 adrenergic agonists and epinephrine as analgesics or as tools to prolong the effect of local anesthetics using a model of cutaneous trunci muscle reflex (pinprick pain) in rats. We showed that subcutaneous 4 adrenergic agonists and epinephrine, as well as the local anesthetic bupivacaine and lidocaine, developed a concentration‐dependent cutaneous analgesia. The rank order of the efficacy of different compounds (ED50; median effective dose) was epinephrine [0.013 (0.012 – 0.014) μmol] > oxymetazoline [0.25 (0.22 – 0.28) μmol] > naphazoline [0.42 (0.34 – 0.53) μmol] = bupivacaine [0.43 (0.37 – 0.50) μmol] > xylometazoline [1.34 (1.25 – 1.45) μmol] > lidocaine [5.86 (5.11 – 6.72) μmol] > tetrahydrozoline [6.76 (6.21 – 7.36) μmol]. The duration of full recovery caused by tetrahydrozoline, oxymetazoline, or xylometazoline was greater (P<0.01) than that induced via epinephrine, bupivacaine, lidocaine, or naphazoline at equianesthetic doses (ED25, ED50, and ED75). Co‐administration of lidocaine (ED50) with 4 adrenergic agonists or epinephrine enhanced the cutaneous analgesic effect. We observed that 4 adrenergic agonists and epinephrine induce analgesia by themselves, and such an effect has a longer duration than local anesthetics. Co‐administration of lidocaine with the adrenergic agonist enhances the analgesic effect, and the cutaneous analgesic effect of lidocaine plus naphazoline (or oxymetazoline) is greater than that of lidocaine plus epinephrine.
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Permeability assessment of small molecules through the blood-brain barrier (BBB) plays a significant role in the development of effective central nervous system (CNS) drug candidates. Since in vivo methods for BBB permeability estimation require a lot of time and resources, in silico and in vitro approaches are becoming increasingly popular nowadays for faster and more economical predictions in early phases of drug discovery. In this work, through application of in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and in silico computational methods we aimed to examine the passive permeability of eighteen compounds, which affect serotonin and dopamine levels in the CNS. The data set was consisted of novel six human dopamine transporter (hDAT) substrates that were previously identified as the most promising lead compounds for further optimisation to achieve neuroprotective effect, twelve approved CNS drugs, and their related compounds. Firstly, PAMPA methods was used to experimentally determine effective BBB permeability (Pe) for all studied compounds and obtained results were further submitted for quantitative structure permeability relationship (QSPR) analysis. QSPR models were built by using three different statistical methods: stepwise multiple linear regression (MLR), partial least square (PLS), and support-vector machine (SVM), while their predictive capability was tested through internal and external validation. Obtained statistical parameters (MLR- R²pred=-0.10; PLS- R²pred=0.64, r²m=0.69, r/2m=0.44; SVM- R²pred=0.57, r²m=0.72, r/2m=0.55) indicated that the SVM model is superior over others. The most important molecular descriptors (H0p and SolvEMt_3D) were identified and used to propose structural modifications of the examined compounds in order to improve their BBB permeability. Moreover, steered molecular dynamics (SMD) simulation was employed to comprehensively investigate the permeability pathway of compounds through a lipid bilayer. Taken together, the created QSPR model could be used as a reliable and fast pre-screening tool for BBB permeability prediction of structurally related CNS compounds, while performed MD simulations provide a good foundation for future in silico examination.
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WHO classified neurological disorders to be among 6.3% of the global disease burden. Among the most central aspects of CNS drug development is the ability of novel molecules to cross the blood–brain barrier (BBB) to reach the target site over a desired time period for therapeutic action. Based on various aspects, brain pharmacokinetics is considered to be one of the foremost perspectives for the higher attrition rate of CNS biologics. Although drug traits are important, the BBB and blood–cerebrospinal fluid barrier together with transporters become the mechanistic approach behind CNS drug delivery. The present review emphasizes neuropharmacokinetic parameters, their importance, an assessment approach and the vast effect of transporters to brain drug distribution for CNS drug discovery.
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Annonacin (1) was isolated from the North American pawpaw (Asimina triloba), as reported earlier from these laboratories. Natural 1 was submitted to the rat aortic ring bioassay for evaluation of antiangiogenic activity and was found to inhibit microvessel growth (IC50 value of 3 μM). 4,10,15,20-Tetraazido derivatives of 1 were prepared by permesylation followed by azide displacement or by iodination followed by azide displacement. The tetraazide derived from mesylation/azidation was antiangiogenic, while that derived from iodination/azidation exhibited no appreciable activity. The membrane permeability of natural 1 was evaluated using the parallel artificial membrane permeability assay and was found to be marginally permeable as compared to several clinically relevant compounds.
Chapter
In this chapter we review methodological approaches to develop a differential diagnosis and to evaluate organic causes of mood disturbance in patients with ADHD, while placing a particular focus on the pediatric population. Many individuals with ADHD experience difficulty with mood disturbance during the course of their illness, making thorough evaluation an important clinical issue. For example, in one population study of 5326 youths with ADHD by Stringaris et al., 38% experienced mood lability, a high percentage that is approximately ten times population rates. In another study by Riley et al. involving 1500 parents of children 6–18 years of age, impairment related to emotional dysregulation in ADHD greatly impacted quality of life, more so than even the attention and hyperactivity deficits themselves. Since practically all psychiatric symptoms can be mimicked by a general medical condition, we explicate the mnemonic MEND A MIND as a useful tool for aiding the clinician at the point of care in formulating a broad differential for organic causes of mood disturbance in patients with ADHD.
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Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupilary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters.
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Prediction of gastrointestinal absorption of thirteen newly synthesized β-hydroxy-β-arylalkanoic acids (HAA) and ibuprofen was performed using PAMPA test. The highest values of PAMPA parameters (%T and Papp) were calculated for 1C, 1B and 2C and these parameters were significantly lower in comparison to ibuprofen. QSPR analysis was performed in order to identify molecular descriptors with the highest influence on %T and − logPapp and to create models which could be used for the design of novel HAA with improved gastrointestinal absorption. Obtained results indicate that introduction of branched side chain, as well as introduction of substituents on one phenyl ring (which disturb symmetry of the molecule) could have positive impact on gastrointestinal absorption. On the basis of these results, six novel HAA were designed and PAMPA parameters %T and − logPapp were predicted by use of selected QSPR models. Designed derivatives should have better gastrointestinal absorption than HAA tested in this study.
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The anticancer potential of ecdysteroids, especially their chemo-sensitizing activity has recently gained a substantial scientific interest. A comprehensive physicochemical profiling was performed for a set of natural or semi-synthetic ecdysteroids (N = 37) to identify a lead compound against central nervous system (CNS) tumors. Calculated properties, such as lipophilicity (clogP), topological polar surface area (TPSA), brain-to-plasma ratio (clogBB) along with the measured blood-brain barrier specific in vitro permeability (logPe) were evaluated in parallel. Compounds with the highest CNS-availability predicted (clogBB > 0.0 and logPe > − 6.0) showed moderate to high lipophilicity (clogP = 3.89–5.25), relatively low TPSA (94.45 Ų), and shared a common apolar 2,3- and 20,22-diacetonide motif (25, 30–33). These ecdysteroids were selected for testing their capacity to sensitize SH-SY5Y neuroblastoma cells to vincristine. All of the five tested compounds exerted a remarkably strong, dose dependent chemo-sensitizing activity: at 2.5–10.0 μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC50 = 39.5 ± 2.9 nM to as low as 0.056 ± 0.03 nM). Moreover, analysis of the combination index (CI) revealed outstanding synergism between ecdysteroids and vincristine (CI50 = 0.072–0.444). Thus, based on drug-likeness, physchem character and in vitro CNS activity, compound 25 was proposed as a lead for further in vivo studies.
Article
The determination of the permeability of drug candidates across the blood-brain barrier (BBB) is a fundamental step during drug discovery programs. The parallel artificial membrane permeability assay (PAMPA) is a high throughput screening tool applied to evaluate the passive permeability and adapted to predict BBB penetration. Herein, a new PAMPA model was developed using an in-house brain lipid extract capable of discriminating BBB permeable from non-permeable compounds. The apparent permeability (Papp) of 18 reference molecules and 10 test compounds was assessed and compared with phosphatidylcholine and commercial porcine polar brain lipid (PBL). The physicochemical selectivity of the in-house brain lipid extract was demonstrated by correlating Papp values with physicochemical properties and its predictive capacity estimated by establishing in vitro-in vivo correlations. The strong correlations achieved between 2% (w/v) in-house lipid extract and PBL for reference (r2 = 0.77) and test compounds (r2 = 0.94) support an equivalent discriminatory capacity and validate the presented model. Moreover, PAMPA studies performed with PBL and in-house lipid extract exhibited a higher correlation with the in vivo parameter logBB (r2 = 0.76 and r2 = 0.72, respectively) than phosphatidylcholine (r2 = 0.51).
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In this work, imidazolium ionic liquids (imidazolium ILs) were employed as the novel chemical permeation enhancers (CPEs) and their performances and mechanisms of action were deeply investigated. Testosterone was used as a model drug to investigate the transdermal delivery enhancement of twenty imdidazolium ILs. The results suggested that the promotion activity connected to the structure and composition of the ILs. The quantitative structure-activity relationship (QSAR) model revealed a good linearity between the electronic properties of ILs and their enhancements. Furthermore, the transepidermal water loss (TEWL) and scanning laser confocal microscope (CLSM) examinations showed the strong improvement of ILs on skin barrier permeability, which were well correlated with the drug penetration profiles. The total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscope (AFM) evaluations of skins indicated that the ILs can disrupt the regular and compact arrangements of the corneocytes, change the surface properties of stratum corneum, and make the skin structure more permeable. Our work demonstrated the significant skin permeation promotion profiles of the imidazolium ILs, which are of great potential in transdermal drug delivery systems.
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The rostral ventrolateral medulla is the primary site of action for clonidine, a centrally acting antihypertensive. In the rostral ventrolateral medulla, clonidine binds not only to alpha-2 adrenergic receptors but also to specific imidazole sites. In order to determine whether a putative imidazole receptor mediates the hypotensive action of clonidine, a series of compounds was tested 1) in vitro for binding affinity at imidazole and alpha-2 sites and 2) in vivo for ability to lower arterial pressure and heart rate when microinjected directly into the rostral ventrolateral medulla. Hypotensive potency was correlated with affinity at imidazole sites (r = 0.84), but not with alpha-2 affinity (r = -0.05). The bradycardia elicited by this series of compounds also correlated with affinity at imidazole receptors (r = 0.89), but not with alpha-2 affinity (r = 0.10). Furthermore, the imidazole idazoxan selectively reversed the fall in arterial pressure elicited by clonidine, whereas SKF-86466, an alpha-2 antagonist which is not an imidazole, failed to attenuate clonidine's action. An imidazole receptor in the rostral ventrolateral medulla appears to mediate the central hypotensive actions of clonidine and related centrally acting imidazoles and may participate in the regulation of arterial pressure and heart rate.
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Imidazoline binding sites (IBS) were proposed to be responsible for some of the pharmacological and therapeutic activities of imidazoline and related compounds and have been classified into two subtypes, I1BS and I2BS. Convergent studies attribute a role in central blood pressure regulation to the I1BS. In contrast, the function of I2BS remains unknown. In the present study, by combining biochemical and molecular biology approaches, we show that 1) microsequencing of I2BS purified from rabbit kidney mitochondria allowed the recovery of four peptide sequence stretches displaying up to 85.7% similarity with human, rat, and bovine monoamine oxidases (MAO)-A and -B; 2) I2BS and MAO displayed identical biophysical characteristics as their activities, measured by [3H]idazoxan binding and [14C]tyramine oxidation, respectively, could not be separated using various chromatographic procedures; and 3) heterologous expression of human placenta MAO-A and human liver MAO-B in yeast, inherently devoid of I2BS and MAO activities, led to the coexpression of [3H]idazoxan binding sites displaying ligand-recognition properties typical of I2BS. These results show definitely that I2BS is located on both MAO-A and -B. The fact that I2BS ligands inhibited MAO activity independently of the interaction with the catalytic region suggests that I2BS might be a previously unknown MAO regulatory site.
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Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research & Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Sandwich, Kent, UK The central nervous system is an important target for many classes of drugs, such as sleep inducers, sedatives, anti-psychotics and -epileptics. For other drug agents, it may be necessary to limit brain penetration to reduce undesirable side effects. Thus there is considerable interest in developing reliable models for the prediction of blood–brain barrier permeation. In this review Joan Abbott expertly discusses models available in vivo, in vitro and in silico. In vivo models are low throughput, whereas currently there still is no standard in vitro screen for assessing brain uptake. The development of robust in silico models is hampered by the availability of sufficient quality and quantity of in vivo data.
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The assessment of transport properties of 23 drug and natural product molecules was made using the in vitro model based on filter-immobilized artificial membranes (filter-IAM), assembled from phosphatidylcholine in dodecane, in buffer solutions at pH 7.4. Five of the compounds were lactones extracted from the roots of the kava-kava plant. Experiments were designed to test the effects of stirring (0–600 rpm) during assays and the effects of varying the assay times (2–15 h). The highly mobile kava lactones permeated in the order dihydromethisticin (40)>yangonin (37)>kavain (34)>methisticin (32)>desmethoxyyangonin (26), the numbers in parentheses being the measured effective permeabilities in units of 10−6 cm/s. By comparison, commercial drugs ranked: phenazopyridine (35)>testosterone (19)>propranolol (13)>ketoconazole (6.3)>piroxicam (2.2)>caffeine (1.7)>metoprolol (0.8)>terbutaline (0.01). In addition to permeability measurements, membrane retention of compounds was determined. Yangonin, desmethoxyyangonin, ketoconazole, and phenazopyridine were more than 60% retained by the artificial membranes containing phospholipids. Stirring during assay significantly increased the observed permeabilities for highly mobile molecules, but had minimal impact on the poorly permeable molecules. The influence of hydrogen bonding was explored by determining permeabilities using filters coated with dodecane free of phospholipids. In the filter-IAM method, concentrations were determined by microtitre plate UV spectrophotometry and by LC–MS. Higher-throughput was achieved with direct UV by the use of 96-well microtitre plate formats and with LC–MS by the use of cassette dosing (five-in-one).
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With the recent development of new hybrid compounds having histamine H3 receptor antagonist with combined histamine N τ -methyltransferase (HMT) inhibitory potency an innovative approach was described in the research of novel lead compounds modulating histaminergic neurotransmission. Several compounds containing an ether moiety derived from the recently published 4-(3-piperidinopropoxy)phenylaminoquinoline derivatives (like FUB 836), were synthesized in this study and tested for their affinity at cloned human histamine H3 (hH3) receptors and on the inhibition of rat HMT. Besides different heterocycles, e.g. nitro- or amino-substituted pyridines, quinolines, benzothiazole or pyrroline, three classes of compounds were produced: heteroaromatic 3-piperidinopropyl ethers, keto- or imino-substituted 4-(3-piperidinopropyl)phenyl ethers and 4-(3-piperidinopropyl)phenyl ethers with substituted (alkyl)aminopyridines. Whereas the (3-piperidinopropoxy)heterocycles showed only moderate activities on both test models, the 4-(3-piperidinopropoxy)phenyl derivatives were identified as potent histamine H3 receptor ligands and/or HMT inhibitors. Ki values up to 0.42 nM were found for the affinity to the hH3 receptor. HMT inhibitory potency was identified with IC50 values about 0.3 μM for the most potent compounds in this series. Comparison of the pyridine-containing derivatives to recently published quinoline analogues showed a decrease in potencies for the pyridines. The dual activity, H3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH3 receptors were higher than their inhibitory HMT potencies. The described new histamine H3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.
Article
Correction to: British Journal of Pharmacology (2004) 143, 649–661. doi:10.1038/sj.bjp.0705964 In the above paper, the incorrect version of Figure 2 was published. The correct version of the figure appears below. The authors apologise for this mistake.
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The performed Quantitative Structure-Mobility Relationship (QSMR) study has investigated relative migration times (RMT) of eleven guanidine/imidazoline derivatives, imidazoline receptor ligands, in capillary electrophoresis (CE) system containing one of cyclodextrins (CDs), α, β, or γ cyclodextrin, using linear and nonlinear modeling methods. The analyzed ligands and their inclusion complexes with the CDs were fully examined and optimized at semi-empirical PM3 level. The density functional theory, such as B3LYP/6-31G+(d,p)/3-21G(d)/STO-3G(d,p)/STO-3G(d), and ab initio theory such as HF/3-21G(d)/STO-3G(d), were applied for molecular descriptors computation of the optimized ligands and their complexes. Predictive performances of the developed QSMR models were tested by use of the cross-validation and external test set prediction. Obtained results for Q(2) values (0.869, 0.911, and 0.966 for CE system containing α, β, and γCD, respectively) and root mean squared error of prediction, RMSEP (0.239, 0.242, and 0.288, for α, β, and γCD, respectively) were proved high predictive power of the proposed models. Finally, multi-target QSMR model (mQSMR), using the ligands descriptors (X) and the relative migration time in presence of αCD (Y1), βCD (Y2), and γCD (Y3), has been created. The mQSMR model can be used as initial screening predictive tool for CE migration behavior of other related guanidine/imidazoline derivatives in presence of αCD, βCD, and γCD.
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The energies of positive and negative ions relative to the neutral atoms are conveniently and accurately expressed for a given atom by a power series in N = n - Z, where n = the number of electrons around the nucleus in a given ionization state and Z = the atomic number of the nucleus. For a neutral atom the electronegativity is defined as χ = (- dE/dN)N = 0 where dE is the energy change which accompanies the change in charge dN and should be expressed in the units energy per electron. Similarly the value of (- dE/dN)N = -1 represents the electronegativity of the singly charged positive ion. The E(N) curve exhibits a discontinuity in slope at N values where there is a transition from one type of atomic orbital to another. If only the first ionization potential and the first electron affinity are known for a given species, χ = (- dE/ dN)N = 0 equivalent to the well-known Mulliken relationship that electronegativity is equal to the average of the ionization potential and the electron affinity.
Article
Estimating log P (logarithm of “1-octanol to water” partition coefficients) as a measure of lipophilicity for organic compounds is of considerable importance in drug discovery. Several methods have been developed for this purpose, each with its own drawbacks and advantages. In this article, a systematic comparison of three well-documented and fully computerized methods has been attempted for a set of nucleosides and bases. The first method (BLOGP) is based on overall molecular properties derived from a molecular orbital calculation to predict log P. The second method (CLOGP) uses fragmental lipophilicity constants with correction factors and treats log P as an additive-constitutive property. The third method (ALOGP) is based on an additivity scheme of atomic lipophilicity constants, with the constitutive factor governed by an elaborate list of atom types. However, none of these methods take into account conformational flexibility or intramolecular hydrogen bonding, which can cause substantial discrepancy between observations and predictions. A comparison of predictions from each of these methods indicates that the atomic contribution method (ALOGP with r = 0.842 and SD = 0.51) is better than other methods (with r = 0.395 and SD = 1.2 for BLOGP and r = 0.713 and SD = 0.93 for CLOGP) for this class of compounds. Our overall assessment is that we do not have, as yet, a highly reliable, fully computerized log P prediction method applicable to flexible heterocycles such as nucleoside analogs. © John Wiley & Sons, Inc.
Article
A relatively simple, widely applicable, and robust in vitro method of predicting blood-brain barrier (BBB) permeability to central nervous system-acting drugs is an increasing need. A cell-based model offers the potential to account for transcellular and paracellular drug diffusional processes, metabolism, and active transport processes, as well as nondefined interactions between a drug and cellular material that may impact upon a membrane's overall permeability profile. Any in vitro BBB cell model to be utilized for the transendothelial BBB permeability screening of potential central nervous system drugs must display reproducible solute permeability, and a number of other general criteria including: a restrictive paracellular barrier; a physiologically realistic cell architecture; the functional expression of key transporter mechanisms; and allow ease of culture to meet the technical and time constraints of a screening program. This article reviews the range of in vitro cell-based BBB models available, including the primary/low passage bovine and porcine brain endothelial cultures as well as the spectrum of immortalized brain endothelial cell lines that have been established. The article further discusses the benefits and limitations of exploiting such systems as in vitro BBB permeability screens. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1681–1698, 2001
Article
Although imidazoline sites have been the subject of research for several years, there is still controversy about their structure, diversity and physiology. The I1 site is thought to exist principally as a binding site and is widely purported to play a role in controlling systemic blood pressure, although this is still unclear. The majority of I2 sites are widely accepted as being allosteric sites on monoamine oxidase; however, even with selective ligands, their exact function remains to be determined. A putative I3 site modulates insulin secretion and could represent the first functional site to be pharmacologically defined with selective agonists and antagonists. The structure and relevance of the proposed endogenous ligand `clonidine-displacing substance' remains elusive. A potential candidate for this substance is agmatine; however, although it is capable of displacing bound clonidine from imidazoline sites, it lacks the functionality ascribed to the clonidine-displacing substance. In this review, Richard M. Eglen and colleagues assess our knowledge of imidazoline sites in the light of recent data.
Article
As datasets are becoming larger, a solution to the problem of variable prediction, this problem is becoming harder. The problem is to define which subset of variables produces optimum predictions. The example studied aims to predict the chromatographic retention of 83 basic drugs on a Unisphere PBD column at pH 11.7 using 1272 molecular descriptors. The goal of this paper is to compare the relative performance of recently developed data mining methods, specifically classification and regression trees (CART), stochastic gradient boosting for tree-based models (Treeboost), and random forests (RF), with common statistical techniques in chemometrics; and genetic algorithms on multiple linear regression (GA-MLR), uninformative variable elimination partial least squares (UVE-PLS), and SIMPLS. The comparison will be performed primarily on predictive performance, but also on the variables found to be most important for the predictions. The results of this study indicated that, individually, GA-MLR (R2=0.93) outperformed all models. Further analysis found that a combination approach of GA-MLR and Treeboost (R2=0.98) further improved these results.
Article
A molecular transform, derived from an equation used in electron diffraction studies, is developed that allows the representation of the three-dimensional structure of a molecule by a fixed number of values. Various atomic properties can be taken into account giving high flexibility to this representation of a molecule. This 3D-MoRSE (Molecule Representation of Structures based on Electron diffraction) code retains important structural features such as the mass (see ref 35) and the amount of branching as evidenced by an investigation of monosubstituted benzene derivatives. Furthermore, this molecular representation was able to distinguish between benzene, cyclohexane, and naphthalene derivatives in a dataset of great structural variety. This molecular representation was used in counterpropagation neural networks to distinguish between dopamine D1 and D2 agonists and to group 31 steroids binding to the corticosteroid binding globulin receptor into compounds of high, medium, and low activity. Great promise is given to this representation of molecular structures for the simulation of infrared spectra as revealed by an investigation of monosubstituted benzene derivatives.
Article
The emergence of multidrug resistance of the currently available antimalarial drugs has led to the need of the discovery and development of new antimalarial compounds. In the present study, we have selected a series of 53 endochin analogs with antimalarial activity against the clinically relevant multidrug resistant malarial strain TM-90-C2B to develop robust QSAR models using different chemometric tools such as stepwise regression, factor analysis followed by multiple linear regression (FA-MLR), factor analysis followed by partial least squares (FA-PLS) analysis, genetic function approximation (GFA) and genetic partial least squares (G/PLS) techniques. We have tried to emphasize on importance of descriptor-thinning prior to feature selection step. For this purpose, we have partitioned the total pool of descriptors into three categories followed by running stepwise regression separately for all three categories of descriptors for selection of variables. Then we have applied genetic methods of model development on the selected pool of descriptors. We have validated the models using different validation parameters to check the statistical quality and reliability of the models. It has been found that models developed from variable selection by stepwise regression followed by GFA and G/PLS are the best two models. This study reflects the importance of descriptor-thinning and noise reduction prior to feature selection for the development of QSAR models. According to the best two models, we interpreted that substitutions with rotatable bond containing groups (e.g., long alkyl chains), limited volume of the molecules, absence of C—R group, presence of electronegative (like —Br) fragments, absence of cycles or rings in the molecules are important for the antimalarial activity. The developed models are believed to comply with the OECD guidelines for QSAR models. The results also confirmed that the QSAR models developed from the reduced pool of descriptors were better than those obtained from the entire pool of descriptors.
Article
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Article
After nearly five decades ``in the making'', QSAR modeling has established itself as one of the major computational molecular modeling methodologies. As any mature research discipline, QSAR modeling can be characterized by a collection of well defined protocols and procedures that enable the expert application of the method for exploring and exploiting ever growing collections of biologically active chemical compounds. This review examines most critical QSAR modeling routines that we regard as best practices in the field. We discuss these procedures in the context of integrative predictive QSAR modeling workflow that is focused on achieving models of the highest statistical rigor and external predictive power. Specific elements of the workflow consist of data preparation including chemical structure (and when possible, associated biological data) curation, outlier detection, dataset balancing, and model validation. We especially emphasize procedures used to validate models, both internally and external
Article
Pre-clinical investigation of some aryl-piperidinyl ether histamine H3 receptor antagonists revealed a strong hERG binding. To overcome this issue, we have developed a QSAR model specially dedicated to H3 receptor ligands. This model was designed to be directly applicable in medicinal chemistry with no need of molecular modeling. The resulting recursive partitioning trees are robust (80-85% accuracy), but also simple and comprehensible. A novel promising lead emerged from our work and the structure-activity relationships are presented.
Article
Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.
Article
Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.
Article
This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as Peff, flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB. Four PAMPA methodologies were evaluated in this study including: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (double sink) model, (3) a PAMPA-BBB (blood-brain barrier) model and (4) a PAMPA-BBB-UWL (unstirred water layer). Additionally, plasma protein binding (PPB) experiments and a Caco-2 assay were performed to determine the unbound fraction in plasma and the efflux ratio, respectively, for subsets of the selected compounds. This information was combined with the obtained PAMPA data in an effort to improve the predictions of LogBB. Taken in aggregate, the results presented, suggest that the PAMPA-BLM parameters are the most important contributors to predict the LogBB. The optimized multiple linear regression (MLR) relationship including the PAMPA-BLM properties demonstrated a slightly improved prediction compared to the model without the PAMPA-BLM parameters. Including the plasma protein binding of 15 compounds resulted in a significantly improved PAMPA-BLM prediction of LogBB, while integrating the efflux ratio with PAMPA-BLM or PAMPA-BBB Peff values, resulted in improved classification of brain permeable [BBB + (LogBB >or= 0)] and impermeable [BBB--(LogBB < 0)] compounds.
Article
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Article
This paper deals with the problem of evaluating the predictive ability of QSAR models and continues the discussion about proper estimates of the predictive ability from an external evaluation set reported in Schüürmann G., Ebert R.-U., et al. External Validation and Prediction Employing the Predictive Squared Correlation Coefficient--Test Set Activity Mean vs Training Set Activity Mean. J. Chem. Inf. Model. 2008, 48, 2140-2145 . The two formulas for calculating the predictive squared correlation coefficient Q2 previously discussed by Schüürmann et al. are one that adopted by the current OECD guidelines about QSAR validation and based on SS (sum of squares) of the external test set referring to the training set response mean and the other based on SS of the external test set referring to the test set response mean. In addition to these two formulas, another formula is evaluated here, based on SS referring to mean deviations of observed values from the training set mean over the training set instead of the external evaluation set.
Article
The histamine H3 receptor plays a regulatory role in the pre-synaptic release of histamine and other neurotransmitters, making it an attractive target for CNS indications including cognitive disorders, narcolepsy, ADHD and pain. As more and more H3 antagonists/H3 inverse agonists progress through the clinic, knowledge is gained to define the profile of the 'ideal' compound in terms of specificity, pharmacokinetic parameters and both duration and magnitude of receptor occupancy. Whether a single compound profile for the treatment of different disorders can be defined remains to be seen.
Article
A new and accurate HPLC method using beta-cyclodextrin chemically bonded to spherical silica particles as chiral stationary phase (CSP) was developed and validated for determination of S-clopidogrel and its impurities R-enantiomer and S-acid as a hydrolytic product. The effects of acetonitrile and methanol content in the mobile phase and temperature on the resolution and retention of enantiomers were investigated. A satisfactory resolution of S-clopidogrel active form and its impurities was achieved on ChiraDex column (5 microm, 4 x 250 mm) at a flow rate of 1.0 ml/min and 17 degrees C using acetonitrile, methanol and 0.01 M potassium dihydrogen phosphate solution (15:5:80 v/v/v) as mobile phase. The detection wavelength was set at 220 nm. The method was validated in terms of accuracy, precision, linearity, and robustness. The limit of detection for R-enantiomer and S-acid were 0.75 and 0.09 microg/ml, respectively, injection volume being 20 microl. Finally, the molecular modeling of the inclusion complexes between the analytes and beta-cyclodextrin was performed to investigate the mechanism of the enantiorecognition and to study the quantitative structure-retention relationships.
Article
The combination of antagonism at histamine H(3) receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4'-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H(3)-antagonists. Starting from these premises, the current work presents an expanded series of histamine H(3) receptor antagonists, characterized by a central 4,4'-biphenyl scaffold, where the structure-activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined. The steric properties and basicity of the terminal groups were modulated in symmetrical compounds, carrying identical substituents, and in asymmetrical compounds, having a piperidine ring at one end and different groups at the other. The length of the linker connecting the biphenyl scaffold to the terminal groups was also modulated. Binding studies at rat and human H(3) receptors evidenced the highest binding affinities for di-basic compounds, in the order of nM concentrations, and that the steric requirements for the two terminal groups are different. Many potent compounds showed good selectivity profiles over the other histamine receptors. Interestingly, some derivatives displayed a moderate ability to inhibit rat brain cholinesterase, for example compound 12 (1-[2-(4'-piperidinomethyl-biphenyl-4-yl)ethyl]piperidine) has a pIC(50)=5.96 for cholinesterase inhibition and high H(3) receptor binding affinity and antagonist potency (pK(i)=8.70; pK(B)=9.28). These compounds can be considered as rigid analogs of a recently reported class of dual-acting compounds and as a promising starting point for the design of new H(3)-antagonists with anti-cholinesterase activity.
Article
Synthesis and biological evaluation of the novel histamine H(3) receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H(3) receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH(3)R K(i)=100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.
Article
Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC(50)=0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC(50) of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.
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The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.
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Histamine-N-methyltransferase (HNMT), the major enzyme for the metabolism of histamine in rat brain, is potently inhibited by 9-amino-1,2,3,4-tetrahydroacridine (tacrine). Structural fragments of tacrine were less potent inhibitors of rat brain HNMT than was tacrine itself. Harmaline and a number of other beta-carbolines inhibited HNMT with IC50 values in the range of 1-10 microM. HNMT inhibition by harmaline was competitive with respect to both substrates, S-adenosylmethionine and histamine (Ki = 1.4 microM). These findings are discussed in the context of mechanisms for HNMT inhibition.
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Low doses of yohimbine (1, 5 and 10 micrograms/kg), injected i.c.v. to spontaneously hypertensive rats as pretreatment, prevented the hypotensive effect of clonidine (standard dose of 5 micrograms/kg). At the opposite, the same doses of yohimbine did not influence the hypotensive effect of clonidine in control groups of normotensive animals (Wistar-Kyoto rats) treated under the same conditions. Interestingly, we observed that the central hypotensive effect of clonidine was greater in the hypertensive animals than in normotensive rats. Thus, we concluded that the central hypotensive effect of clonidine is affected by very low doses of yohimbine in spontaneously hypertensive rats and not in normotensive control animals. The yohimbine insensitive effect might be due to the action of clonidine on one type of medullary receptors specific to the imidazoline structure. On the physiopathological side, it seems therefore that, in hypertensive animals, there is a yohimbine sensitive mechanism, perhaps an alpha-2 adrenoceptor stimulating effect, which is nonexistent in normotensive animals.
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To check whether the central hypotensive effect of alpha adrenergic agonists is linked with the stimulation of alpha-2 receptors, such drugs were administered directly to the nucleus reticularis lateralis, which is an important site for the hypotensive action of clonidine. These experiments were carried out by microinjections (0.5 microliter on each side) in normotensive cats anesthetized with pentobarbital. alpha-Methylnorepinephrine, a selective alpha-2 agonist (0.1-10 micrograms/kg) had no hypotensive effect in this region, whereas potent alpha-1 agonists such as cirazoline (0.01-1 micrograms/kg) and ST 587 (1-10 micrograms/kg), like clonidine, produced dose-dependent hypotensive effects. Our results suggest that alpha-2 selective catecholamines are not active in the nucleus reticularis lateralis region, whereas imidazolines induce a hypotensive effect whatever their affinity for one subtype of alpha adrenoceptors. Therefore, there may be some form of structure-activity relationship which would indicate the existence, in this particular region of the medulla oblongata, of sites preferring the imidazoline structure.