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Green and white chemistry are vital to revolutionizing the chemical industry through their unparalleled potential to enhance sustainability and efficiency. In this study, nine sustainability tools of both green and white metrics, including green analytical procedure index (GAPI), ComplexGAPI, analytical greenness, analytical greenness metric for sample preparation, Analytical Eco-Scale (ESA), analytical method greenness score, high-performance liquid chromatography- environmental assessment tool (HPLC-EAT), analytical method volume intensity, and blue applicability grade index (BAGI), have been developed for appraising environmental friendliness for both innovative and straightforward mean centering of ratio spectra (MCR) and reversed-phase high-performance liquid chromatography (RP-HPLC) strategies utilized for concurrent analysis and separation of cyclopentolate (CYC) and C12 and C14 homologs of benzalkonium chloride (BNZ) in pure and ophthalmic solution. The mobile phase, formed of buffer phosphate and acetonitrile (35:65, v/v), was adjusted to pH 6.3, and 215-nm UV detection was used. The experimental flow rate was 2.0 mL min -1 , and the analytical column was L11 Inertsil Ph-3 (150 mm × 4.6 mm, 5 µm). All sequences were run at 25°C in the column oven. The MCR approach effectively resolved the drug's spectral overlapping. CYC and BNZ employed this approach at 227.5 and 220.4 nm, respectively. As part of the HPLC analysis, an isocratic method was employed with phosphate buffer and acetonitrile in the mobile phase at 35:65. A correlation coefficient greater than 0.999 was observed between the calibration curves for the HPLC and MCR methods in the ranges of 20-320 µg mL -1 and 5-30 µg mL -1 for all drugs. The technique yields excellent primary recovery rates, ranging from 97.2% to 100.5%. The recommended approach has been validated according to International Council for Harmonization guidelines., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Introduction: This study aimed to determine the in vitro and in silico effects of some natural and synthetic molecules on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glucosidase enzymes., Background: Alzheimer's disease (AD) and Type II diabetes mellitus (T2DM) are considered the most important diseases of today's world. However, the side effects of therapeutic agents used in both diseases limit their use. Therefore, developing drugs with high therapeutic efficacy and better pharmacological profile is important., Objectives: This study sets out to determine the related enzyme inhibitors used in treating AD and T2DM, considered amongst the most important diseases of today's world., Methods: In the current study, the in vitro and in silico effects of dienestrol, hesperetin, Lthyroxine, 3,3',5-Triiodo-L-thyronine (T3) and dobutamine molecules on AChE, BChE and α - glycosidase enzyme activities were investigated., Results: All the molecules showed an inhibitory effect on the enzymes. The IC 50 and K i values of the L-Thyroxine molecule, which showed the strongest inhibition effect for the AChE enzyme, were determined as 1.71 μM and 0.83 ± 0.195 μM, respectively. In addition, dienestrol, T3, and dobutamine molecules showed a more substantial inhibition effect than tacrine. The dobutamine molecule showed the most substantial inhibition effect for the BChE enzyme, and IC 50 and K i values were determined as 1.83 μM and 0.845 ± 0.143 μM, respectively. The IC 50 and K i values for the hesperetin molecule, which showed the strongest inhibition for the α -glycosidase enzyme, were determined as 13.57 μM and 12.33 ± 2.57 μM, respectively., Conclusion: According to the results obtained, the molecules used in the study may be considered potential inhibitor candidates for AChE, BChE and α-glycosidase., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Kınkor ( Ferulago stell ata ) is Turkish medicinal plant species and used in folk medicine against some diseases. As far as we know, the data are not available on the biological activities and chemical composition of this medicinal plant. In this study, the phytochemical composition; some metabolic enzyme inhibition; and antidiabetic, anticholinergic, and antioxidant activities of this plant were assessed. In order to evaluate the antioxidant activity of evaporated ethanolic extract (EEFS) and lyophilized water extract (WEFS) of kınkor ( Ferulago stellata ), some putative antioxidant methods such as DPPH· scavenging activity, ABTS •+ scavenging activity, ferric ions (Fe 3+ ) reduction method, cupric ions (Cu 2+ ) reducing capacity, and ferrous ions (Fe 2+ )-binding activities were separately performed. Furthermore, ascorbic acid, BHT, and α-tocopherol were used as the standard compounds. Additionally, the main phenolic compounds that are responsible for antioxidant abilities of ethanol and water extracts of kınkor ( Ferulago stell ata ) were determined by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Ethanol and water extracts of kınkor ( Ferulago stell ata ) demonstrated effective antioxidant abilities when compared to standards. Moreover, ethanol extract of kınkor ( Ferulago stell ata ) demonstrated IC 50 values of 1.772 μg/mL against acetylcholinesterase (AChE), 33.56 ± 2.96 μg/mL against α-glycosidase, and 0.639 μg/mL against α-amylase enzyme respectively.

The tropane alkaloids (TAs) hyoscyamine and scopolamine function as acetylcholine receptor antagonists and are used clinically as parasympatholytics to treat neuromuscular disorders in humans. While TAs are synthesized in a small subset of plant families, these specialized metabolites are only accumulated in limited quantities in plant organs. The complex chemical structures of these compounds make their industrial production by chemical synthesis very challenging, Therefore, the supply of these TAs still relies on intensive farming of Duboisia shrubs in tropical countries. Many adverse factors such as climate fluctuations and pandemics can thus influence annual world production. Based on the landmark microbial production of the antimalarial semi-synthetic artemisinin, the Smolke group recently developed a yeast cell factory capable of de novo synthesizing hyoscyamine and scopolamine, thus paving the way for an alternative production of these compounds., (© 2020 Wiley-VCH GmbH.)

Dithiocarbamates are considered as an important motif owing to its extensive biological applications in medicinal chemistry. The synthesis of this framework can easily be achieved via a one-pot reaction of primary/secondary amines, CS 2 , and alkyl halides under catalyst-free conditions or sometimes in the presence of a base. By virtue of its colossal pharmacological scope, it has been an evolving subject of interest for many researchers around the world. The present review aims to highlight various synthetic approaches for dithiocarbamates with the major emphasis on medicinal attributes of these architectures as leads in the drug discovery of small molecules such as HDAC inhibitor, lysine-specific demethylase 1 (LSD1) down-regulator, kinase inhibitor (focal adhesion kinase, pyruvate kinase, Bruton's tyrosine kinase), carbonic anhydrase inhibitor, DNA intercalators, and apoptosis-inducing agents. Moreover, recent medicinal advancements in the synthesis of dithiocarbamate derivatives as anticancer, antifungal, antibacterial, anti-Alzheimer, antitubercular, anti-glaucoma, anti-cholinergic, antihyperglycemic, anti-inflammatory activities have been elaborated with notable examples., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two kinds of hydroxypropyl β-cyclodextrin nanohybrid monoliths were synthesized and applied in capillary electrochromatography with UV detection. One column was fabricated by concurrently using glycidyl methacrylate-bonded hydroxypropyl β-cyclodextrin (GMA-HP-β-CD), sodium 3-mercaptopropanesulphonate, and alkoxysilanes in the "one-pot" process. The other was prepared by free radical polymerization of GMA-HP-β-CD, vinylmethylcyclosiloxane, ethylene dimethacrylate, and 2-acrylamido-2-methyl propane sulfonic acid. Compared to the former hybrid monolith, the latter one displayed improved enantiomeric separation. For ten adrenergic drugs, six anticholinergic drugs, two antidepressants, six azoles, and one antihistamine enantiomeric separation was obtained on the monolith synthesized by free radical polymerization. Twelve out of twenty-five drugs were baseline-separated. Especially, anisodamine with two chiral centers was successfully separated with resolution values of 3.06, 2.11, and 2.17. The nanohybrid monoliths were characterized by optical microscopy, scanning electron microscopy, FT-IR, nitrogen adsorption analysis, and thermogravimetric analysis. Relative standard deviation values less than 5% were obtained through run-to-run, day-to-day, and column-to-column investigations (n = 3). Graphical abstract Schematic representation of two kinds of hydroxypropyl β-cyclodextrin nanohybrid monoliths based on "one-pot" approach (route I) and free radical polymerization approach (route II), respectively.

Here we report the design of an enzyme-inspired metal-organic framework (MOF), 1 -OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF ( 1 ), with mixed 2,2'-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy) 2 (dcbpy)] + (ppy = 2-phenylpyridine) sites to afford 1 -OTf-Ir with both Lewis acid and photoredox sites. 1 -OTf-Ir effectively catalyzed reductive cross-coupling of N -hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives. 1 -OTf-Ir enabled catalytic synthesis of anticholinergic drugs Pheniramine and Chlorpheniramine.

Lower urinary tract symptoms (LUTS) induced by anticholinergic drug action impair the QOL of patients and are associated with a poor prognosis. Therefore, it is expedient to develop methods of predicting the anticholinergic side effects of drugs, which we aimed to achieve in this study using a quantitative structure-activity relationship (QSAR) and docking study with molecular operations environment (MOE; Molecular Simulation Informatics Systems [MOLSIS], Inc.) In the QSAR simulation, the QSAR model built using the partial least squares regression (PLS) and genetic algorithm-multiple linear regression (GA-MLR) methods showed remarkable coefficient of determination (R 2 ) and XR 2 values. In the docking study, a specific relationship was identified between the adjusted docking score (-S) and bioactivity (pKi) values. In conclusion, the methods developed could be useful for in silico risk assessment of LUTS, and plans are potentially applicable to numerous drugs with anticholinergic activity that induce serious side effects, limiting their use.

Recently, the pyridazine nucleus has been widely studied in the field of particular and new medicinal factors as drugs acting on the cardiovascular system. Additionally, a number of thienopyridazines have been claimed to possess interacting biological macromolecules and pharmacological activities such as NAD(P)H oxidase inhibitor, anticancer, and identified as a novel allosteric modulator of the adenosine A1 receptor. The literature survey demonstrates that coumarin, 1,2-pyrazole benzothiazole, and 1,3- thiazole scaffolds are the most versatile class of molecules. In this study, a series of substituted pyrazole[3,4-d]pyridazine derivatives (2a-n) were prepared, and their structures were characterized by Mass analysis, NMR, and FT-IR. These obtained pyrazole[3,4-d]pyridazine compounds were very good inhibitors of the carbonic anhydrase (hCA I and II) isoenzymes and acetylcholinesterase (AChE) with K i values in the range of 9.03 ± 3.81-55.42 ± 14.77 nM for hCA I, 18.04 ± 4.55-66.24 ± 19.21 nM for hCA II, and 394.77 ± 68.13-952.93 ± 182.72 nM for AChE, respectively. The possible inhibition mechanism of the best-posed pyrazole[3,4-d]pyridazine and pyrazole-3-carboxylic acid derivatives and their interaction with catalytic active pocket residues were determined based on the calculations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of this work was to investigate the enzyme inhibition, antioxidant activity, and phenolic compounds of Lecokia cretica (Lam.) DC. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase enzymes were strongly inhibited by the L. cretica extracts. IC 50 values for the three enzymes were found as 3.21 mg/mL, 2.1 mg/mL, and 2.07 mg/mL, respectively. Antioxidant activities were examined in both aqueous and ethanol (EtOH) extracts using CUPRAC, FRAP, and DPPH method. Also, the phenolic compounds of the endemic plant were identified and quantified by using HPLC/MS/MS. According to the results, the extracts have remarkable antioxidant activities. The most abundant phenolic acids of L. cretica in EtOH extract were determined as quinic acid (12.76 mg/kg of crude extract), chlorogenic acid (3.39 mg/kg), and malic acid (2.38 mg/kg)., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3'R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3'R-SGM was metabolized to 2R3'R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3'R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3'R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3'R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3'R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3'R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3'R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A useful synthesis of (R)-[N-methyl- 3 H]quinuclidinyl benzilate methiodide is described with the product characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), tritium nuclear magnetic resonance (NMR), and mass spectrometry (MS). Several methods are provided to purify the radioligand, and its storage and stability are also discussed., (© 2019 John Wiley & Sons, Ltd.)

Five oxypropanol amine derivatives that four of them are novel have been synthesized with high yields and practical methods. in vitro antibacterial susceptibility of Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus strains to synthesized substances were evaluated with agar well-diffusion method by comparison with commercially available drugs. Most of the bacteria were multidrug resistant. It was concluded that these compounds are much more effective than reference drugs. These eugenol bearing oxypropanolamine derivatives were also effective inhibitors against α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with K i values in the range of 0.80 ± 0.24-3.52 ± 1.01 µM for hCA I, 1.08 ± 0.15-3.64 ± 0.92 µM for hCA II, 5.18 ± 0.84-12.46 ± 2.08 µM for α-glycosidase, and 11.33 ± 2.83-32.81 ± 9.73 µM for AChE, respectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr 3 to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅ + ) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) radical scavenging activity, Fe 3+ and Cu 2+ reducing activities and ferrous (Fe 2+ ) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ± 0.73-59.45 ± 14.97 nM against AChE and 4.31 ± 1.93-44.14 ± 2.19 nM against α-glycosidase., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bunias erucago belongs to the Brassicaceae family, which represents a forgotten crop of the Euro-Mediterranean area. The aim of the present study was to determine the glucosinolate profile in different plant parts and biological properties (antioxidant, anticholinesterase, and cytotoxic activities) of the isolates containing glucosinolate breakdown products. The chemical profiles were determined by using HPLC-PDA-MS/MS of desulfoglucosinolates and GC-MS of glucosinolate degradation products. The analysis of B. erucago showed the presence of seven glucosinolates: gluconapin ( 1 ), glucoraphasatin ( 2 ), glucoraphenin ( 3 ), glucoerucin ( 4 ), glucoraphanin ( 5 ), glucotropaeolin ( 6 ), and glucosinalbin ( 7 ). The total glucosinolate content ranged from 7.0 to 14.6 µmol/g of dry weight, with the major glucosinolate glucosinalbin in all parts. The antioxidant activity of all volatile isolates was not notable. At a tested concentration of 227 μg/mL, flower hydro-distillate (FH) showed good AChE inhibition, i.e., 40.9%, while root hydro-distillate (RH) had good activity against BChE, i.e., 54.3%. FH showed the best activity against both tested human bladder cancer cell lines, i.e., against T24 after 72 h, which have IC 50 of 16.0 μg/mL, and against TCCSUP after 48 h with IC 50 of 7.8 μg/mL, and can be considered as highly active. On the other hand, RH showed weak activity against tested cancer cells.

Coumarins and essential oils are the major components of the Apiaceae family and the Zosima genus. The present study reports anticholinesterase and antioxidant activities of extracts and essential oils from aerial parts, roots, flowers, fruits and coumarins-bergapten ( 1 ); imperatorin ( 2 ), pimpinellin ( 3 ) and umbelliferone ( 4 )-isolated of the roots from Zosima absinthifolia . The investigation by light and scanning electron microscopy of the structures of secretory canals found different chemical compositions in the various types of secretory canals which present in the aerial parts, fruits and flowers. The canals, present in the aerial parts, are characterized by terpene hydrocarbons, while the secretory canals of roots, flowers and fruits include esters. Novel data of a comparative study on essential oils constituents of aerial parts, roots, flowers and fruits of Z. absinthfolia has been presented. The roots and fruits extract showed a high content of total phenolics and antioxidant activity. The GC-FID and GC-MS analysis revealed that the main components of the aerial parts, roots, flowers and fruits extracts were octanol (8.8%), octyl octanoate (7.6%), octyl acetate (7.3%); trans -pinocarvyl acetate (26.7%), β-pinene (8.9%); octyl acetate (19.9%), trans-p -menth-2-en-1-ol (4.6%); octyl acetate (81.6%), and ( Z )-4-octenyl acetate (5.1%). The dichloromethane fraction of fruit and flower essential oil was characterized by the highest phenolics level and antioxidant activity. The dichloromethane fraction of fruit had the best inhibition against butyrylcholinesterase enzyme (82.27 ± 1.97%) which was higher then acetylcholinesterase inhibition (61.09 ± 4.46%) of umbelliferone. This study shows that the flowers and fruit of Z. absinthifolia can be a new potential resource of natural antioxidant and anticholinesterase compounds.

To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [ 3 H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.

In the presence of chiral organic catalysts, the optically active 4H-chromine was synthesized from the multicomponent condensation of 5,5-dimethylcyclohexane-1,3-dione with malononitrile and methylene-active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL-III polarimeter and their structures were confirmed by the X-ray spectroscopic analysis method. These optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles were effective inhibitors of α-glycosidase, the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with K i values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 μM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 μM for hCA II, 18.16 ± 3.18 to 66.57 ± 1.36 μM for α-glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 μM for AChE., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

The synthesis, characterization, aggregation behavior, theoretical studies, and investigation of antimicrobial, antidiabetic, and anticholinergic properties of 4-(2-(5-amino-4-(4-bromophenyl)-3-methyl-1H-pyrazol-1-yl)ethoxy)phthalonitrile (2) and its soluble aminopyrazole-substituted peripheral metallo (Mn, Co, and Ni)-phthalocyanine complexes (3-5) are reported for the first time. The synthesized compounds and phthalocyanine complexes were characterized spectroscopically. The new phthalonitrile derivative (2) and its peripheral metallophthalocyanine complexes (3-5) were found to be effective inhibitors of α-glycosidase, acetylcholinesterase (AChE), human carbonic anhydrase I and II isoforms (hCA I and II), and butyrylcholinesterase (BChE) with K i values in the range of 1.55 ± 0.47 to 10.85 ± 3.43 nM for α-glycosidase, 8.44 ± 0.32 to 21.31 ± 7.91 nM for hCA I, 11.73 ± 2.82 to 31.03 ± 4.81 nM for hCA II, 101.62 ± 26.58 to 326.54 ± 89.67 nM for AChE, and 68.68 ± 11.15 to 109.53 ± 19.55 nM for BChE. This is the first study of peripherally substituted phthalocyanines containing an aminopyrazole group as potential carbonic anhydrase enzyme inhibitor. Also, the antimicrobial activities of the synthesized compounds were evaluated against six microorganisms (four bacteria and two Candida species) using the broth microdilution method. The gram-positive bacteria were detected to be more sensitive than gram-negative bacteria and yeasts in the synthesized compounds., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

A series of classical and newly synthesized thymol bearing oxypropanolamine compounds were synthesized and characterized. Their in vitro antibacterial activity on A. baumannii, P. aeruginosa, E. coli and S. aureus strains were investigated with agar well diffusion method. The results were compared with commercially available drug active compounds. As well as 3a, 3b and 3c have the most significant antibacterial effect among all the tested compounds; approximately all of them have more antibacterial activity than the reference drugs. These novel thymol bearing oxypropanolamine derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase enzymes (AChE) with K i values in the range of 463.85-851.05 µM for α-glycosidase, 1.11-17.34 µM for hCA I, 2.97-17.83 µM for hCA II, and 13.58-31.45 µM for AChE, respectively., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reverse cholesterol transport (RCT) plays an important role in cholesterol and lipid metabolism. Regulating the activities of key transporters and receptors in RCT, such as ATP-binding cassette transporter A1 (ABCA1), helps to prevent atherosclerotic cardiovascular disease. In this study, we used an ABCA1 promoter luciferase reporter assay to screen 20,000 compounds for ABCA1 upregulators. Compound E3317 (N-(6-butylbenzo[d]thiazol-2(3H)-ylidene)-3-(N-(2-cyanoethyl)sulfamoyl)benzamide)) was identified as a positive hit with an EC 50 value of 0.2 μM in ABCA1p-LUC HepG2 cells. Thus, we hypothesized that E3317 might have cholesterol- and lipid metabolism-regulating effects through ABCA1 upregulation. E3317 significantly increased ABCA1 mRNA and protein expression in hepatic L02 cells and RAW264.7 macrophages. E3317 promoted cholesterol efflux to apolipoprotein A-I in RAW264.7 macrophages and significantly decreased lipid accumulation in oxidized low-density lipoprotein-induced murine RAW264.7 macrophages. Further studies using ABCA1 siRNA showed that the promotion of cholesterol efflux and decrease of lipid accumulation by E3317 depended on ABCA1 expression. Mechanistic studies indicated that E3317 regulated ABCA1 expression via activating nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays an important role in the regulation of glucose homeostasis and lipid metabolism. The structure of E3317 was docked in the ligand-binding domain of PPARγ (PBD code: 4EMA) to find the key binding amino acids. Site mutation assays confirmed that Y327 and F363 were the key PPARγ binding epitopes of E3317. Our results revealed that E3317 upregulates ABCA1 expression and thereby promotes cholesterol efflux. E3317 may regulate ABCA1 expression through PPARγ. Our findings provide a new compound, E3317, which may have beneficial cardiovascular effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

[Ni(C 11 H 9 N 2 O 5 ) 2 (H 2 O) 2 ]•3(C 3 H 7 NO) (1) and [Co(C 11 H 9 N 2 O 5 ) 2 (H 2 O) 2 ]•3(C 3 H 7 NO) (2) are synthesized and characterized by elemental analysis, FT-IR spectra, magnetic susceptibility, and thermal analysis. In addition, the crystal structure of Ni(II) complex is presented. Both complexes show distorted octahedral geometry. In 1 and 2, metal ions are coordinated by two oxygen atoms of salicylic residue and two nitrogen atoms of maleic amide residue from two ligands, and two oxygen atoms from two water molecules. In this paper, both compounds showed excellent inhibitory effects against human carbonic anhydrase (hCA) isoforms I, and II, α-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compounds 1 and 2 had Ki values of 18.36 ± 4.38 and 26.61 ± 7.54 nM against hCA I and 13.81 ± 3.02 and 29.56 ± 6.52 nM against hCA II, respectively. On the other hand, their Ki values were found to be 487.45 ± 54.18 and 453.81 ± 118.61 nM against AChE and 199.21 ± 50.35 and 409.41 ± 6.86 nM against BChE, respectively., (© 2018 Wiley Periodicals, Inc.)

In this work, the enantiomeric separation of ten anticholinergic drugs was first examined on two derivative polysaccharide chiral stationary phases (CSPs), i.e., Chiralpak ID and Chiralpak IA in the normal phase mode. Except for scopolamine hydrobromide, the remaining nine analytes could be completely separated with good resolutions using both columns under the optimized mobile phase conditions. And the enantiomeric discrimination ability of the studied CSPs towards nine analytes was in the order of Chiralpak ID > Chiralpak IA. The influences of organic modifier types, alcohol content, and base/acid additives on the enantiomeric separation were evaluated and optimized. According to the experimental results, the effect of the structures of analytes on enantiomeric separation was discussed. Additionally, the chiral recognition mechanisms were proposed based on the thermodynamic analysis of the experimental data., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work reported a new method of design for the immobilization of acetylcholinesterase (AChE) based on its molecular structure to improve its sensitivity and stability. The immobilization binding site on the surface of AChE was determined using MOLCAD's multi-channel functionality. Then, 11 molecules ((+)-catechin, (-)-epicatechin, (-)-gallocatechin, hesperetin, naringenin, quercetin, taxifolin, (-)-epicatechin gallate, flupirtine, atropine, and hyoscyamine) were selected from the ZINC database (about 50 000 molecules) as candidate affinity ligands for AChE. The fluorescence results showed that the binding constant K b between AChE and the ligands ranged from 0.01344 × 10 4 to 4.689 × 10 4 M -1 and there was one independent class of binding site for the ligands on AChE. The AChE-ligand binding free energy ranged from -12.14 to -26.65 kJ mol -1 . Naringenin, hesperetin, and quercetin were the three most potent immobilized affinity ligands. In addition, it was confirmed that the binding between the immobilized ligands only occurred at a single site, located in an inactive area on the surface of AChE, and did not affect the enzymatic activity as shown through a competition experiment and enzyme assay. This method based on protein surface structural recognition with high sensitivity and stability can be used as a generic approach for design of the enzyme immobilization and biosensor development.

G protein-coupled receptors (GPCRs) are integral membrane proteins and represent the largest class of drug targets. During the past decades progress in structural biology has enabled the crystallographic elucidation of the architecture of these important macromolecules. It also provided atomic-level visualization of ligand-receptor interactions, dramatically boosting the impact of structure-based approaches in drug discovery. However, knowledge obtained through crystallography is limited to static structural information. Less information is available showing how a ligand associates with or dissociates from a given receptor, whose importance is in fact increasingly recognized by the drug research community. Owing to recent advances in computer power and algorithms, molecular dynamics stimulations have become feasible that help in analyzing the kinetics of the ligand binding process. Here, we review what is currently known about the dynamics of GPCRs in the context of ligand association and dissociation, as determined through both crystallography and computer simulations. We particularly focus on the molecular basis of ligand dissociation from GPCRs and provide case studies that predict ligand dissociation pathways and residence time.

Background: Research on natural bioactive compounds has increased exponentially over the last decades. The discovery of new phytochemicals that possess pharmaceutical properties is useful in the development of therapeutic alternatives. The nerolidol (3,7,11-trimetil-1,6,10-dodecatrien-3-ol or 3,7,11-trimetildodeca-1,6,10-trien-3-ol) has been extensively studied for its therapeutic potential because of its pharmacological activities in the treatment of neurodegenerative diseases., Method: All articles and patents regarding nerolidol and its pharmacological properties were revised, focusing mainly on the important properties in the treatment of neurodegenerative diseases. A thorough search in article databases (Science Direct, MEDLINE/PubMed, Scopus and Scielo) and patent database (WIPO, EPO, ESPTO, LATIPAT and INPI) was performed over the course of this study., Results: Several studies stood out for their relevance regarding the treatment of neurodegenerative diseases. Nerolidol demonstrated anticholinesterasic, antioxidant, antinociceptive, anti-inflammatory and anxiolytic activities, thus classifying it as a promising phytochemical for the development of therapeutic drugs., Conclusion: Analysis suggested that nerolidol is a promising target for new drugs and treatment of neurodegenerative diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Three kinds of sulfated β-cyclodextrin (S-β-CD), including a single isomer, heptakis-6-sulfato-β-cyclodextrin (HS-β-CD), degree of substitution (DS) of 7, which was synthesized in our laboratory and another two commercialized randomly substituted mixtures, a sulfated β-cyclodextrin with DS of 7 to 11, as well as a highly sulfated-β-cyclodextrin with DS of 12 to 15, were used for the enantioresolution of 12 drugs (the β-blockers, phenethylamines, and anticholinergic agents) in capillary electrophoresis. The enantioseparation under varying concentrations of S-β-CD and background electrolyte pH were systematically investigated and compared. Based on the experimental results, the effect of the nature of S-β-CD and analyte structure on the enantioseparation is discussed., (© 2017 Wiley Periodicals, Inc.)

Marigold ( Calendula officinalis L.) is one of the most common and widespread plants used medicinally all over the world. The present study aimed to evaluate the anti-acetylcholinesterase activity of marigold flowers, detect the compounds responsible and perform chemical analysis of marigold commercial products. Analysis of 23 varieties of C. officinalis flowers introduced into Siberia allowed us to select the Greenheart Orange variety due to the superior content of flavonoids (46.87 mg/g) and the highest inhibitory activity against acetylcholinesterase (IC 50 63.52 µg/mL). Flavonoids, isorhamnetin and quercetin derivatives were revealed as potential inhibitors with the application of high-performance liquid chromatography (HPLC) activity-based profiling. Investigation of the inhibitory activity of isorhamnetin glycosides demonstrated the maximal potency for isorhamnetin-3- О -(2'',6''-di-acetyl)-glucoside (IC 50 51.26 μM) and minimal potency for typhaneoside (isorhamnetin-3- O -(2'',6''-di-rhamnosyl)-glucoside; IC 50 94.92 µM). Among quercetin derivatives, the most active compound was quercetin-3- О -(2'',6''-di-acetyl)-glucoside (IC 50 36.47 µM), and the least active component was manghaslin (quercetin-3- O -(2'',6''-di-rhamnosyl)-glucoside; IC 50 94.92 µM). Some structure-activity relationships were discussed. Analysis of commercial marigold formulations revealed a reduced flavonoid content (from 7.18-19.85 mg/g) compared with introduced varieties. Liquid extract was the most enriched preparation, characterized by 3.10 mg/mL of total flavonoid content, and infusion was the least enriched formulation (0.41 mg/mL). The presented results suggest that isorhamnetin and quercetin and its glycosides can be considered as potential anti-acetylcholinesterase agents., Competing Interests: The authors declare no conflict of interest.

Indoles constitute extensively explored heterocyclic ring systems with wide range of applications in pathophysiological conditions that is, cancer, microbial and viral infections, inflammation, depression, migraine, emesis, hypertension, etc. Presence of indole nucleus in amino acid tryptophan makes it prominent in phytoconstituents such as perfumes, neurotransmitters, auxins (plant hormones), indole alkaloids etc. The interesting molecular architecture of indole makes them suitable candidates for the drug development. This review article provides an overview of the chemistry, biology, and toxicology of indoles focusing on their application as drugs. Our effort is to corroborate the information available on the natural indole alkaloids, indole based FDA approved drugs and clinical trial candidates having diverse therapeutic implementations. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Acetylcholine affects the target cellular function via muscarinic and nicotinic cholinergic receptors that are seen to exist in humans. Both the cholinergic receptors are G-protein coupled receptors (GPCRs) that perform cardinal functions in humans. Anti-muscarinic drugs, particularly the ones that target M1 subtype (mAChR1), have consistently shown to kill unicellular pathogenic eukaryotes like Acanthamoeba spp. As the M1 receptor subtype has not been reported to be expressed in the above protist, the presence of an ancient form of the M1 muscarinic receptor was inferred. Bioinformatic tools and experimental assays were performed to establish the presence of a ligand-binding site. A search for sequence homology of amino acids of human M1 receptor failed to uncover an equivalent ligand-binding site on Acanthamoeba, but structural bioinformatics showed a hypothetical protein L8HIA6 to be a receptor homolog of the human mAChR1. Immunostaining with an anti-mAChR1 antibody showed cellular staining. Growth assays showed proliferation and lethal effects of exposure to mAChR1 agonist and antagonist respectively. With the recent authentication of human mAChR1 structure and its addition to the database, it was possible to discover its structural analog in Acanthamoeba; which could explain the effects of anticholinergics observed in the past on Acanthamoeba spp. The discovery of a receptor homolog of human mAChR1 on Acanthamoeba with future studies planned to show its expression and binding to cholinergic agonist and antagonist would help clarify its role in the biology of this protist pathogen.

Scopolia tangutica (S. tangutica) is a traditional Chinese medicinal plant used for antispasmodics, anesthesia, analgesia and sedation. Its pharmacological activities are mostly associated with the antagonistic activity at muscarinic acetylcholine receptors (mAchRs) of several known alkaloids such as atropine and scopolamine. With our recent identification of four hydroxycinnamic acid amides from S. tangutica, we hypothesized that this plant may contain previously unidentified alkaloids that may also contribute to its in vivo effect. Herein, we used a bioassay-guided multi-dimension separation strategy to discover novel mAchR antagonists from S. tangutica. The core of this approach is to use label-free cell phenotypic assay to first identify active fractions, and then to guide purification of active ligands. Besides four tropanes and six cinnamic acid amides that have been previously isolated from S. tangutica, we recently identified two new tropanes, one new cinnamic acid amide, and nine other compounds. Six tropane compounds purified from S. tangutica for the first time were confirmed to be competitive antagonists of muscarinic receptor 3 (M3), including the two new ones 8 and 12 with IC 50 values of 1.97 μM and 4.47 μM, respectively. Furthermore, the cinnamic acid amide 17 displayed 15-fold selectivity for M1 over M3 receptors. These findings will be useful in designing lead compounds for mAchRs and elucidating mechanisms of action of S. tangutica.

Nitrogen mustard (NM) is a bifunctional alkylating agent that is highly reactive in the skin causing extensive tissue damage and blistering. In the present studies, a modified cutaneous murine patch model was developed to characterize NM-induced injury and to evaluate the efficacy of an indomethacin pro-drug in mitigating toxicity. NM (20μmol) or vehicle control was applied onto 6mm glass microfiber filters affixed to the shaved dorsal skin of CD-1 mice for 6min. This resulted in absorption of approximately 4μmol of NM. NM caused localized skin damage within 1 d, progressing to an eschar within 2-3 d, followed by wound healing after 4-5 d. NM-induced injury was associated with increases in skin thickness, inflammatory cell infiltration, reduced numbers of sebocytes, basal keratinocyte double stranded DNA breaks, as measured by phospho-histone 2A.X expression, mast cell degranulation and increases in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Wound healing was characterized by epidermal hyperplasia and marked increases in basal cells expressing proliferating cell nuclear antigen. A novel indomethacin-anticholinergic prodrug (4338) designed to target cyclooxygenases and acetylcholinesterase (AChE), was found to markedly suppress NM toxicity, decreasing wound thickness and eschar formation. The prodrug also inhibited mast cell degranulation, suppressed keratinocyte expression of iNOS and COX-2, as well as markers of epidermal proliferation. These findings indicate that a novel bifunctional pro-drug is effective in limiting NM mediated dermal injury. Moreover, our newly developed cutaneous patch model is a sensitive and reproducible method to assess the mechanism of action of countermeasures., (Copyright © 2016. Published by Elsevier Inc.)

Recently, cholinesterase-based biosensors are widely used for assaying anticholinergic compounds. Primarily biosensors based on enzyme inhibition are useful analytical tools for fast screening of inhibitors, such as organophosphates and carbamates. The present review is aimed at compilation of the most important facts about cholinesterase based biosensors, types of physico-chemical transduction, immobilization strategies and practical applications.

A series of 4-hydroxycoumarin-derived compounds 8a-p containing N-benzyl-1,2,3-triazole motif were designed as AChE inhibitors. The title compounds were obtained conveniently using multicomponent click reaction. The in vitro anticholinesterase evaluation of synthesized compounds against AChE and BuChE showed that some of them are potent and selective inhibitors of AChE. Among them, 2-chlorobenzyl derivative 8k showed the most potent activity against AChE (IC50  = 0.18 μm). Its activity was also superior to that of standard drug tacrine. The kinetic study and molecular docking simulation of the most potent compound 8k were also described., (© 2015 John Wiley & Sons A/S.)

Tiotropium bromide is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease. The crystal structures of this compound and its monohydrate have been previously solved and published. However, in this paper, we showed that those structures contain some major errors. Our methodology based on combination of the solid-state nuclear magnetic resonance (NMR) spectroscopy and quantum mechanical gauge-including projector-augmented wave (GIPAW) calculations of NMR shielding constants enabled us to correct those errors and obtain reliable structures of the studied compounds. It has been proved that such approach can be used not only to perform the structural analysis of a drug substance and to identify its polymorphs, but also to verify and optimize already existing crystal structures., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

This study was intended to design an orally disintegrating tablet (ODT) formulation that can mask the extremely bitter and metallic taste of phencynonate HCl by novel ion-exchange resins. The drug-resin complexes (DRCs) were prepared and characterized by scanning electron microscopy, X-ray powder diffraction and differential scanning calorimetry. In vitro properties (dissolution, wetting time and disintegration time) and in vivo behavior (disintegration time and taste-masking effect) in healthy volunteers of the prepared ODTs were also investigated. The drug was changed from the crystal structure to the amorphous form in the DRC. Compared with commercial tablets, the in vitro and in vivo disintegration of optimized DRC-loaded ODTs with a drug-resin ratio of 1:1 was greatly improved and better palatability with a low bitterness index (0.33) was obtained. The current DRC-loaded ODT could promise a good way to mask the unpleasant taste of certain drugs and accordingly improve the patient compliance.

Background: Penehyclidine hydrochloride (PHC) is a new anticholinergic drug, which has been shown to have a good curative effect for sepsis. Beta arrestins have been demonstrated to play important roles in sepsis. This study is to investigate the effects of PHC on pulmonary microvascular permeability and on expressions of beta arrestins in lung injury induced by the cecal ligation and puncture (CLP) procedure., Materials and Methods: Thirty healthy female mice were randomly divided into three groups (n = 10 each): sham operation group (control group), CLP group (CLP group), and PHC 0.45 mg/kg group (PHC group). In the PHC group, mice were given an intraperitoneal injection of PHC 0.45 mg/kg 1 h before surgery. Mice in the other two groups received an intraperitoneal injection of the same volume of normal saline. At 12 h after surgery, serum and bronchoalveolar lavage fluid were collected to examine lung permeability index. The lung tissue samples were collected to examine expressions of myosin light chain kinase (MLCK), vascular endothelial-cadherin (VE-cadherin), vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), NF-κB, and beta arrestins., Results: Compared with the control group, pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions were significantly increased, whereas VE-cadherin and beta-arrestin protein expressions were obviously decreased in CLP group. Furthermore, compared with the CLP group, PHC group markedly decreased pulmonary microvascular permeability, MPO activity, NF-κB, VCAM-1, and MLCK expressions, and increased expressions of VE-cadherin and beta arrestins., Conclusions: This study suggests that in the CLP-induced lung injury model, PHC could reduce pulmonary microvascular permeability by upregulating expressions of beta arrestins., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cholinergic tone contributes to airflow obstruction in chronic obstructive pulmonary disease. Accordingly, anticholinergics are effective bronchodilators by blocking the muscarinic M3 receptor on airway smooth muscle. Recent evidence indicates that acetylcholine also contributes to airway inflammation. However, which muscarinic receptor subtype(s) regulates this process is unknown. In this study, the contribution of the M1, M2 and M3 receptor subtypes to cigarette smoke-induced airway inflammation was investigated by exposing muscarinic receptor subtype deficient mice to cigarette smoke for 4 days. In wild-type mice, cigarette smoke induced an increase in macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid. Neutrophilic inflammation was higher in M1(-/-) and M2(-/-) mice compared to wild-type mice, but lower in M3(-/-) mice. Accordingly, the release of keratinocyte-derived chemokine (KC), monocyte chemotactic protein-1 and interleukin-6 was higher in M1(-/-) and M2(-/-) mice, and reduced in M3(-/-) mice. Markers of remodelling were not increased after cigarette smoke exposure. However, M3(-/-) mice had reduced expression of transforming growth factor-β1 and matrix proteins. Cigarette smoke-induced inflammatory cell recruitment and KC release were also prevented by the M3-receptor selective antagonist 1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) in wild-type mice. Collectively, our data indicate a pro-inflammatory role for the M3 receptor in cigarette smoke-induced neutrophilia and cytokine release, yet an anti-inflammatory role for M1 and M2 receptors.

Three new lanostanoid triterpenes, 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (1), 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester (2), and 3β,15β-dihydroxy-7,11,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester (3) were isolated from the EtOAc extract of the fruiting bodies of Ganoderma tropicum. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopy as well as MS. The bioassay of inhibitory activity against acetylcholinesterase (AChE) of these isolates was evaluated and compound 2 exhibited definite inhibitory activity against AChE.

The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage., (Copyright © 2011 John Wiley & Sons, Ltd.)

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

The aim of the present study was to mask the bitterness of propiverine hydrochloride (P-4) by converting it to propiverine free base. Fine granules comprising the free base, which was converted from P-4 by desalination, were prepared. By using Fourier transform infrared spectroscopy, thermogravimetry-differential thermal analysis, and powder X-ray diffraction spectra, we confirmed that P-4 had been converted into propiverine free base by desalination during the manufacturing process. Furthermore, the conversion into free base appeared to result in decreased solubility, and both the taste testing sensor and tasting volunteers determined that it masked the bitterness of P-4. On using the gustatory sensation test, the bitterness of the P-4 fine granules was confirmed to be weakened. The dissolution rate and bioavailability of fine granules of the free base were compared with tablets of P-4. The dissolution rate and bioavailability of the fine granules and tablets were almost the same. We successfully masked the taste of P-4 by converting it into free base using a manufacturing process that was suitable for commercial manufacturing.

The effects of three concentrations of aqueous-ethanolic extract, 10 nM atropine and saline on muscarinic receptors were tested on two groups of non-incubated (group 1; n = 7) and incubated tracheal chains with propranolol and chlorpheniramine (group 2; n = 6). The EC₅₀ of higher concentration of the extract (2 µg mL⁻¹) in group 2 was significantly greater than those of group 1 (p < 0.01). The maximum response obtained in the presence of all concentrations of extract in groups 1 and 2 were lower than saline (p < 0.05 to 0.001). There were parallel rightward shifts in the concentration response curves obtained for all concentrations of the extract in group 2. There was significant and positive correlation between the concentrations and the values of EC₅₀ in group 1 (p < 0.05) and group 2 (p < 0.001). These results indicate an anti-cholinergic effect of Zataria multiflora Boiss on the tracheal chains of guinea pigs. A β-adrenoceptor stimulatory effect for the plant was also suggested.

Animal model of depression was developed by means of chronic exposure of rat pups to anticholinergic drugs (Atropine, Scopolamine) during the early life period from postnatal day 7 (P7) and/or 14 (P14) to P21 and/or P28, respectively. Such procedure resulted in lasting behavioral changes that were evident long after drug discontinuation and persisted at mature age (2-3 month period). Behavioral changes included most indices of open field behavior. Modeled animals exhibited significant depression of locomotor activity certified by sharp reduction of the number of crossed squares, rising of a head and vertical standings. Grooming behavior was also significantly decreased. Frequency of center entrance and the time of staying in the center of open field were sharply shortened. Modeled animals exhibited complete loss of exploratory motivation which wasn't related to the enhancement of fear emotion so far as values of incidence of urination and defecation remained unchangeable. These findings indicate that postnatal exposure of rat pups to Atropine and/or Scopolamine induces lasting behavioral "despai"' or "refractory loss of interest" at mature age. In sum animal model of depression which are characterized by super sensitivity of brain muscarinic cholinergic system exhibit more depressed behavioral items in open field than other types of animal models of depression. These data imply the preference of muscarinic cholinergic super sensitivity for the development of depressive state and therefore they are very significant for both basic science and clinical research issues.

Objectives: This study was conducted to test whether our novel combination (i.e. microanalysis) of near-infrared (NIR) spectroscopy and humidity-controlled 96-well plate, reported in a previous issue of this journal, can be successfully applied to quantitative evaluation of the pseudopolymorphic transformation of imidafenacin., Methods: Sample powders of a drug compound were placed in a humidity-controlled 96-well plate containing various saturated salt solutions, and stored at 35°C. NIR spectra were collected using a Fourier transform-NIR spectrometer in combination with a fiber-optic probe. The actual hydrate contents of samples were determined by using thermal gravimetric analysis (TGA). A series of sets of NIR spectra and TGA data were used to establish a calibration model with which to predict the contents of monohydrate by partial least-squares regression (PLS)., Key Findings: The PLS calibration model analysis showed that the plots of NIR predicted values to the actual values gave a straight line with correlation coefficients of 0.9868 and 0.9936, respectively, for the 96-well plate and glass-bottle uses. The model using the 96-well plate was therefore able to predict the transformation of imidafenacin in one form to another form as quantitatively as the conventional model using glass bottles., Conclusion: The present study confirmed that our microanalysis quantitatively predicts the pseudopolymorphic transformation of our tested drug in small amounts and suggests that this particular method is a simple and convenient one that may be efficiently applied to polymorphic and pseudopolymorphic studies of a hygroscopic drug candidate, at even earlier development stages than the conventional method using glass bottles., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

A series of 1-substituted imidazoles 1a-d and 2a-d were synthesized and screened for antispasmodic and antidiarrheal activities. Antispasmodic activity was tested at various concentrations on isolated tissue preparations; concentration-response curves were plotted and compared with atropine. All compounds were found to inhibit contraction of the guinea pig ileum. Castor oil-induced diarrhea model in rats was used for evaluation of antidiarrheal activity. Parameters such as intestinal transit and volume of intestinal fluid were measured for antidiarrheal activity at 40 mg kg-1 dose and compared with the standard drug loperamide at 6 mg kg-1 dose. Defecation frequency in the test group was found to be significantly lower (p < 0.01) compared to the control group and comparable with that of the standard. The present study reveals that the compounds exert antidiarrheal activity through possible inhibition of intestinal movement and reduction of capillary permeability in the abdominal cavity.