Convergent synthesis and preliminary biological evaluations of the stilbenolignan (±)-aiphanol and various congeners

Treatment of an equimolar mixture of stilbene 7 and cinnamyl alcohol 8 with silver carbonate in acetone–benzene afforded a ca. 2 : 1 : 2 : 1 mixture of the stilbenolignan (±)-aiphanol (1) and congeners 2–4 each of which show significant anti-angiogenic and COX-2 inhibitory properties.

COX-2 inhibition and pain management: a review summary

Cyclooxygenase-2 selective inhibitors have long been regarded as potent anti-inflammatory drugs for the treatment of arthritis, osteoarthritis and dysmenorrhea. The reports of cardiovascular risk and the subsequent withdrawal of rofecoxib, and recently valdecoxib, has called the therapeutic potential of coxibs into question. Currently, according to the latest decisions of the US Food and Drug Administration and European Medicines Agency, the approval of valdecoxib has been refused for 1 year due to an increased rate of cardiovascular risks and serious skin reactions. There are restrictions concerning the use of all other coxibs. The short-time use of coxibs, however, in anti-inflammatory tr…

1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase.

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference comp…

Characterization of a Computerized Assay for Rapid and Easy Determination of Leukocyte Adhesion to Endothelial Cells

We report on a facile and rapid computerized in-vitro assay for the quantification of leukocyte adhesion to endothelial cells under static conditions using bovine polymorphonuclear neutrophils (PMN) or human leukaemic Mono Mac 6 cells (MM6) and bovine aorta endothelial cells (BAEC). Images of leukocytes adherent to BAEC monolayers grown in microtiter plates were obtained by a digital camera attached to a conventional microscope and transferred to the public domain NIH ImageJ program for analysis. Using individually adapted program routines adherent leukocytes are easily discriminated and reproducibly quantified. The results obtained with our assay correspond to previous findings and demonst…

Synthesis and Evaluation of a Novel Series of Pyrrolizine Derivatives as Dual Cyclooxygenase-1 and 5-Lipoxygenase Inhibitors

The aim of our study was to investigate structure activity relationship following the replacement of the 6-phenyl substituent at the 6,7-diaryl-2,3-dihydropyrrolizine template by various heteroaromatic residues. In this context we developed a new, efficient, and highly sensitive test method for the screening of dual cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors. We used human platelets as a source of COX-1 and human PMNLs as a source of 5-LOX. Both cell types were isolated from the same volume of blood. PGE2 and LTB4 respectively were determined by highly selective and sensitive ELISA kits, using monoclonal antibodies. For a single determination at most 0.5 mL whole blood i…

ChemInform Abstract: Regioisomeric 3-, 4-, and 5-Aminomethylisoxazoles: Synthesis and Muscarinic Activity.

Muscarinic Properties of Compounds Related to Arecaidine Propargyl Ester

A series of new analogues of the arecaidine propargyl ester (CAS 35516-99-5, APE, 1a) with alcohols consisting of 4 or 5 carbon atoms were investigated at muscarinic receptor subtypes. The muscarinic activity of the quaternary and tertiary salts of the APE-related compounds were assayed on the isolated guinea-pig ileum (M 3 receptor subtype) and guinea-pig left atria (M 2 receptor subtype) as well as on rabbit isolated vas deferens (M 1 receptor subtype). The structural variations made in the APE molecule, replacing the triple bond in the ester side chain with structures such as double bond, an allene moiety, a single bond, a cyclopropyl group or two triple bonds should alter the selectivit…

Structural Approaches to Explain the Selectivity of COX-2 Inhibitors: Is There a Common Pharmacophore?

The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs. This review will focus on the structural features needed to achieve COX-2 selectivity. Five structural classes can be identified together with a class bearing little or no resemblance to one another in their molecular structure. The most interesting point is the very distinct structure/activity relationship. On the one hand only minor modifications to a particular compound induce a drastic change in its COX selectivity and on the other hand the structural prerequisites in …

Non-steroidal anti-inflammatory agents. Part 23. Synthesis and Pharmacological Activity of Enaminones which inhibit both bovine cyclooxygenase and 5-lipoxygenase

The synthesis and stereochemical characteristics of pyrrolidino-, isoquinolino- and indolo-enaminones 2–11 are reported. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5-lipoxygenase using intact bovine polymorphonuclear leucocytes. Except compound 2c′ which is a well-balanced dual inhibitor of both enzymes, all other enaminone derivatives are weak inhibitors of both cyclooxygenase and 5-lipoxygenase. Structure-activity relationships of the enaminones in relation to known anti-inflammatory drugs are discussed.

5,6,7-Trimethoxy-2,3-dihydro-1H,8H-benzo[a]pyrrolo[3,4-c]carbazole-1,3-dione dimethyl sulfoxide solvate

The crystal structure of the title compound, C21H16N2O5·C2H6OS, was determined to investigate the electrocyclic reactivity of 3,4-di­aryl-1H-pyrrole-2,5-diones (3,4-bisarylmal­eimides) to the yield corresponding carbazole derivatives.

ChemInform Abstract: COX-1/COX-2 Inhibitors Based on the Methanone Moiety.

Novel 3-Azaindolyl-4-arylmaleimides Exhibiting Potent Antiangiogenic Efficacy, Protein Kinase Inhibition, and Antiproliferative Activity

Tumor growth and metastasis are highly associated with the overexpression of protein kinases (PKs) regulating cell growth, apoptosis resistance, and prolonged cell survival. This study describes novel azaindolyl-maleimides with significant inhibition of PKs, such as VEGFR, FLT-3, and GSK-3β which are related to carcinogenesis. Furthermore, these compounds exhibit high kinase selectivity and potent inhibition of angiogenesis and cell proliferation, offering versatile options in cancer treatment strategies.

NSAR: Klassifizierung und Wirkspektrum: Eine heterogene Arzneistoffklasse

NSAR sind etablierte Arzneistoffe zur Behandlung entzundlicher Erkrankungen wie z.B. der rheumatoiden Arthritis, der Osteoarthritis und der Arthrose. In den letzten Jahren ist durch die Entwicklung von selektiven COX-2-Hemmstoffen der Arzneischatz bereichert worden. Allerdings gibt es immer mehr Anhaltspunkte, dass mit den selektiven COX-2-Hemmern hinsichtlich der Vertraglichkeit keine den klassischen NSAR deutlich uberlegene Substanzgruppe erhalten wurde.So mahnte die amerikanische Arzneimittelbehorde FDA den Rofecoxib (Vioxx ®)-Hersteller wegen „falscher, unausgewogener oder irrefuhrender Aussagen” ab, nachdem sich herausgestellt hatte, dass Daten zur Unvertraglichkeit in den publizierten…

ChemInform Abstract: Benzimidazoles as NMDA Glycine-Site Antagonists: Study on the Structural Requirements in 2-Position of the Ligand.

A series of different substituted benzimidazole derivatives has been synthesized and evaluated for the ability to displace [3H]MDL-105,519 to rat cortical membranes. Two benzimidazole-2-carboxylic acids 9 b and 9 c, in this substitution pattern not yet described as glycine antagonists, showed IC50 values of 0.89 microM (9 b) and 38.0 microM (9 c). Replacement of the carboxylate function in 2-position by a sulfonic acid moiety appreciably increased solubility, but decreased the affinity giving evidence for the strong need of the carboxylate group within the ligand. Further structure-activity studies using benzimidazole-2-one derivatives with an acetic acid moiety adjacent to a ring nitrogen …

A Novel Series of 2-Carboxytetrahydroquinolines Provides New Insights into the Eastern Region of Glycine Site NMDA Antagonists

A series of potent 4-substituted tetrahydroquinolines has been synthesized and biologically tested in order to refine the eastern region of the pharmacophore model for glycine site NMDA antagonists concerning the assessment of lipophilicity, flexibility, and hydrogen bonding. Displacement studies on rat cortical membranes using [ 3 H]-5,7-dichlorokynurenic acid as a radioligand indicated that binding affinities are markedly enhanced when additional hydrogen-accepting groups are introduced into the eastern region of the 2-carboxytetrahydroquinolines. Among the most potent ligands were some urea, sulfonylurea, and crown ether compounds as interesting leads for new diagnostics, especially for …

ChemInform Abstract: Pyrrolidino Enaminones Structurally Related to Gyrase Inhibitors: Synthesis, Cyclization and Pharmacological Activity.

ChemInform Abstract: Design and Pharmacology of Quinuclidine Derivatives as M2-Selective Muscarinic Receptor Ligands.

COX-1/COX-2 inhibitors based on the methanone moiety

This paper focuses on the synthesis and the in vitro testing of dual COX-1/COX-2 inhibitors. Starting from structures of non-steroidal anti-inflammatory drugs (NSAIDs) the diaryl methanone element was chosen as a lead. Modifications were carried out on this scaffold to obtain potent inhibitors of the COX enzymes. The N-(2-aroylphenyl)sulphonamides and -amides were studied in detail, and to consolidate the data evaluated the corresponding 3- and 4-regioisomers were also investigated. The potency and the enzyme selectivity were varied by structural modifications of the lead.

ChemInform Abstract: Regioisomeric 5(3)-Aminomethyl-3(5)-phenylisoxazoles: Synthesis, Spectroscopic Discrimination, and Muscarinic Activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens. Regioisomere 5(3)-Aminomethyl-3(5)-phenyl-isoxazole: Synthese, spektroskopische Unterscheidung und muskarinische Aktivitat Es werden verschiedene Verfahren zur regioselektiven Darstellung von 5(3)-Aminomethyl-3(5)-phenyl-isoxazolen beschrieben, die anhand ihrer spektroskopischen Daten, insbesondere der massenspektrosk…

ChemInform Abstract: Non-Steroidal Antiinflammatory Agents. Part 23. Synthesis and Pharmacological Activity of Enaminones which Inhibit Both Bovine Cyclooxygenase and 5-Lipoxygenase.

Synthesis, labelling and evaluation of hydantoin-substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N-methyl-d-aspartate receptor

The N-methyl- d-aspartate (NMDA) receptor as a type of ionotropic glutamatergic receptors is essential for physiological processes such as learning, memory and synaptic plasticity. A glutamate-induced overactivation of these receptors, accompanied by increased intracellular calcium concentration, causes cell injury and leads to a large number of acute or chronic neurological disorders, such as stroke, trauma, Parkinson's disease and Alzheimer's disease. In an attempt to visualise the glutamatergic neurotransmission in vivo with positron emission tomography, novel fluoroethoxy- and methoxy-substituted reference compounds based on the lead structure of a hydantoin-substituted indole-2-carboxy…

Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions.

For decades neuroreceptor research has focused on the development of NMDA glycine-site antagonists, after Johnson and Ascher found out in 1987 about the co-agonistic character of this achiral amino acid at the NMDA receptor. Contrary to the inhibitory glycine receptor (glycine(A)) the glycine binding site on the NMDA receptor (glycine(B)) is strychnine-insensitive. A great diversity of diseases showing a disturbed glutamate neurotransmission have been linked to the NMDA receptor. Glycine site antagonists have been investigated for acute diseases like stroke and head trauma as well as chronic ones like dementia and chronic pain.

ChemInform Abstract: Non-Steroidal Antiinflammatory Agents. Part 22. Pyrrolidino-enaminones with an Acetic Acid Function at C-3: Synthesis and Inhibition of the Enzymes Cyclooxygenase and 5-Lipoxygenase.

Benzimidazoles as NMDA Glycine-Site Antagonists: Study on the Structural Requirements in 2-Position of the Ligand

A series of different substituted benzimidazole derivatives has been synthesized and evaluated for the ability to displace [3H]MDL-105,519 to rat cortical membranes. Two benzimidazole-2-carboxylic acids 9 b and 9 c, in this substitution pattern not yet described as glycine antagonists, showed IC50 values of 0.89 microM (9 b) and 38.0 microM (9 c). Replacement of the carboxylate function in 2-position by a sulfonic acid moiety appreciably increased solubility, but decreased the affinity giving evidence for the strong need of the carboxylate group within the ligand. Further structure-activity studies using benzimidazole-2-one derivatives with an acetic acid moiety adjacent to a ring nitrogen …

Synthesis and Muscarinic Activity of Isoxazole-substituted 1,2,5,6-Tetrahydropyridines

Hinweise für den Patienten

Bei vielen chronischen Erkrankung hat sich gezeigt, dass ihre Bewaltigung einfacher ist, wenn sich die Patienten mit der Erkrankung befassen. Eine besondere Rolle spielen die Selbsthilfegruppen. Sie bieten Informationen und Aufklarung uber die Erkrankungen, durch Kontakt mit ebenfalls Betroffenen konnen die Patienten der Isolation der Krankheit entfliehen. Es ist haufig eine grose Hilfe, wenn die Patienten frei uber die Krankheit aber auch die damit verbundenen psychischen und sozialen Probleme sprechen konnen. Es ist zudem auch fur den betreuenden Arzt hilfreich und herausfordernd zugleich, einen aufgeklarten und informierten Patienten zu behandeln. Zuletzt konnen Selbsthilfegruppen zwisch…

4-(3-Hydroxy-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2,5-dihydro-1H-pyrrole-2,5-dione

The title compound, C20H19NO7, crystallizes in the space group Pna21. X-ray analysis shows the compound has the desired 3′-hydroxy and 4′-methoxy substitution pattern, as in the natural template combretastatin A-4.

Sozialmedizinische Aspekte der Epilepsie

Die Epilepsie ist eine schon im Altertum bekannte Erkrankung, deren besondere Bedeutung sich in den ausfuhrlichen Beschreibungen ausert. Der Begriff, der sich aus dem griechischen „epilambanein“ fur „ergriffen uberwaltigt sein“ ableitet und seine Bezeichnung im Corpus hippocraticum als „morbus sacer“, die heilige Krankheit, deuten schon die Haltung der Bevolkerung zu dieser Erkrankung an, obwohl Arzte im Altertum wie Hippokrates oder Galen durchaus von einer normalen organischen Ursache der Erkrankung ausgingen. Auch wenn die Kenntnisse uber Genese, Pathophysiologie und Klinik der Epilepsie heute viel genauer sind als bei vielen anderen zerebralen Erkrankungen, bleibt immer noch ein Rest vo…

SAR-studies of γ-secretase modulators with PPARγ-agonistic and 5-lipoxygenase-inhibitory activity for Alzheimer’s disease

Abstract We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure–activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79 μM (Aβ42), 0.3 μM (5-lipoxygenase) and an EC50 value of 4.64 μM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a …

Nonsteroidal Antiinflammatory Agents, XVIII: C-5 Functionalized 6,7-Diphenyl-2,3-dihydro-1H-pyrrolizines as Inhibitors of Bovine Cyclooxygenase and 5-Lipoxygenase

6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizines with functional groups at position 5 of the heterocyclic moiety were synthesized and tested. To determine their antiinflammatory activity bovine blood was used as enzyme source for the cyclooxygenase and 5-lipoxygenase, respectively. The iminoxy acetic acid derivative and the iminotetrazole selectively inhibit the 5-lipoxygenase, all the other compounds show medium or low affinity to the active sites of cyclooxygenase and 5-lipoxygenase. In general all compounds inhibit 5-lipoxygenase more effectively than cyclooxygenase. Concerning the inhibition of 5-lipoxygenase the most active compounds found are equipotent to the corresponding pro…

ChemInform Abstract: Cyclooxygenase Inhibitors - Current Status and Future Prospects

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase and subsequent downstream synthetases. Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2. Both isoenzymes transform arachidonic acid to prostaglandins, but differ in their distribution and their physiological roles. Meanwhile, the responsible genes and their regulation have been clarified. COX-1, the pre-dominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow and platelet aggregation. In contrast, the inducible for…

ChemInform Abstract: Nonsteroidal Antiinflammatory Agents. Part 18. C-5 Functionalized 6,7- Diphenyl-2,3-dihydro-1H-pyrrolizines as Inhibitors of Bovine Cyclooxygenase and 5-Lipoxygenase.

ChemInform Abstract: Synthesis and Muscarinic Activity of Isoxazole-Substituted 1,2,5,6- Tetrahydropyridines.

Methyl [4-methoxy-3-(methylsulfonyloxy)benzoyl]formate

The crystal structure of the title compound, C11H12O7S, confirms an earlier proposal concerning the regioselectivity of electrophilic substitution reactions of mesyl guaiacol.

The pyrrole moiety as a template for COX-1/COX-2 inhibitors

Aroyl- and thiophene-substituted pyrrole derivatives have been synthesized as a new class of COX-1/COX-2 inhibitors. The inhibition of COX-1 was evaluated in a biological system using bovine PMNLs as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of the concentration of arachidonic acid metabolites was performed by HPLC for COX-1 and RIA for COX-2. Variation of the substitution pattern led to a series of active compounds which showed inhibition for COX-1 and COX-2. Structural requirements for the development of COX-1/COX-2 inhibitors are discussed.

Betreuung des Patienten

Eine adaquate Patientenbetreuung hat einen hohen Stellenwert fur die Behandlung rheumatischer Erkrankungen, da bei den chronischen Prozessen dem Patienten unbedingt vermittelt werden mus, das es mehrere Moglichkeiten gibt, den Krankheitsverlauf zu kontrollieren sowie den Schmerz zu reduzieren bzw.zu beseitigen. Die Patienten sind selbst am besten in der Lage, den Wirkstoff herauszufinden, der die Schmerzsymptome bei einem Minimum an unerwunschten Effekten optimal lindert. Voraussetzung fur die notwendige Mitarbeit des Patienten bei der Therapie und deren Akzeptanz sind ausreichende Informationen von Seiten des Arztes zum Arzneistoff, zu den moglichen unerwunschten Wirkungen und eine realist…

Neue Antiepileptika in der Entwicklung. Substanzen mit neuen Wirkmechanismen

Unbestritten ist, dass sich durch den Einsatz von Antiepileptika der 2. Generation die Situation fur Epilepsiepatienten entscheidend verbessert hat. Dennoch bleibt ein Patientenklientel, bei dem keine ausreichende Anfallskontrolle erreicht wird, das therapierefraktar ist oder im Verlauf der Behandlung wird. Weiterentwicklungen von AEDs aus der 2. Generation (“follow-up compounds”) bzw. Wirkstoffe mit neuen Strukturen und Wirkmechanismen konnten zukunftig diese Lucke fullen.

Profile and molecular modeling of 3-(indole-3-yl)-4-(3,4,5-trimethoxyphenyl)-1 H-pyrrole-2,5-dione (1) as a highly selective VEGF-R2/3 inhibitor.

We report on selectivity profiling of 1 in a panel of 20 protein kinases and molecular modeling indicating 1 to be highly active and selective for VEGF-R2/3. Sequence alignment analysis and detailed insights into the ATP binding pockets of targeted protein kinases from the panel result in a unique structural architecture of VEGF-R2 mainly caused by the hydrophobic pocket I, determining the molecular basis for activity and selectivity of 1.

Anatomische und neurophysiologische Grundlagen epileptischer Anfälle

Zum Verstandnis der Pathophysiologie und der Phanomenologie der Epilepsien und der epileptischen Anfalle sollen zunachst die hierfur wichtigen Aspekte der Architektur und Funktion des menschlichen Hirns beschrieben werden. Das Gehirn besteht aus den zwei Groshirnhemispharen, dem Kleinhirn und dem Hirnstamm. Im anatomischen Schnitt lassen sich die grau-gelb gefarbte Rinde (Kortex) und die im Marklager gelegenen Kerngebiete der Basalganglien von einer weisen Substanz abgrenzen. Die graue Substanz besteht vorwiegend aus den Nervenzellen, wahrend die weise Substanz von den bemarkten Bahnen gebildet wird. Die Rinde selbst ist durch Einfaltelungen in Furchen (Sulci) und Windungen (Gyri) raumlich …

Variations of acidic functions at position 2 and substituents at positions 4, 5 and 6 of the indole moiety and their effect on NMDA-glycine site affinity

The synthetic procedures to obtain indole derivatives with different acidic functions at position 2 of the indole are reported. The synthesised and tested derivatives comprise 5-tetrazolyl, 1,3,4-oxadiazol-5-yl-2-one, and indole-2-carboxylic acid amides with 5-aminotetrazole, methanesulphonamide and trifluoromethanesulphonamide moieties. The binding affinity was evaluated using [3H]MDL 105,519 and pig cortical brain membranes. In general, compounds with acidic functions different from a carboxylic acid moiety are less potent than indole-2-carboxylic acid derivatives. Also, the 4,6-dichloro substitution pattern was compared to 5-tert-butyl derivatives and compounds not substituted in the ben…

Editorial: Pharmazie in unserer Zeit 4/2007

ChemInform Abstract: Non-Steroidal Antiinflammatory Agents. Part 19. E-2-Pyrrolizin-5-yl Acrylic Acids as Potent Dual or Selective Inhibitors of Bovine Cyclooxygenase and 5-Lipoxygenase.

Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors

The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in…

3-(1H-Indol-3-yl)-4-(3,4,5-trimethoxyphenyl)-2,5-dihydro-1H-pyrrole-2,5-dione

The crystal structure of the title compound, C21H18N2O5, was determined in order to study the electrocyclic reactivity of 3,4-di­aryl-1H-pyrrole-2,5-dione derivatives. Intermolecular hydrogen bonds form sheets.

Non-steroidal Anti-inflammatory Agents, Part 19:E-2-Pyrrolizin-5-yl Acrylic Acids as Potent Dual or Selective Inhibitors of Bovine Cyclooxygenase and 5-Lipoxygenase

The pyrrolizinyl substituted acrylic acid derivatives represent another class of dual and selective inhibitors of cyclooxygenase and 5-lipoxygenase. By modifying their substitution pattern at the phenyl moiety of C-6 the balance between the activity against cyclooxygenase and against 5-lipoxygenase can be shifted. Structure-activity relationships are discussed. Compound 6k is the most potent and well-balanced dual inhibitor of both enzymes, while the highest selectivity of lipoxygenase inhibition was found for 6j. The activity and selectivity of compounds with an additional sulfur moiety depend on the oxidation status of this atom, giving an indication of the discussed coupling between pero…

ChemInform Abstract: 1-Pyrrolines (3,4-Dihydro-2H-pyrroles) as a Template for New Drugs

Dihydroisocoumarins, Naphthalenes, and Further Polyketides from Aloe vera and A. plicatilis: Isolation, Identification and Their 5-LOX/COX-1 Inhibiting Potency

The present study aims at the isolation and identification of diverse phenolic polyketides from Aloe vera (L.) Burm.f. and Aloe plicatilis (L.) Miller and includes their 5-LOX/COX-1 inhibiting potency. After initial Sephadex-LH20 gel filtration and combined silica gel 60- and RP18-CC, three dihydroisocoumarins (nonaketides), four 5-methyl-8-C-glucosylchromones (heptaketides) from A. vera, and two hexaketide-naphthalenes from A. plicatilis have been isolated by means of HSCCC. The structures of all polyketides were elucidated by ESI-MS and 2D 1H/13C-NMR (HMQC, HMBC) techniques. The analytical/preparative separation of 3R-feralolide, 3′-O-β-d-glucopyranosyl- and the new 6-O-β-d-glucopyranosyl…

Non-Steroidal Anti-Inflammatory Agents, Part 20[1] Method for Testing Non-Steroidal Anti-Inflammatories: The Modified Hen's Egg Chorioallantoic Membrane Test (HET-CAM Test) Compared to Other Procedures

The delay of onset of irritation phenomena at the chorioallantoic membrane of incubated hen's eggs, a parameter for anti-inflammatory activity, was determined for the pharmaceutical substances diclofenac, flufenamic acid, ibuprofen, indomethacin, ketoprofen, piroxicam, phenylbutazone, salicylic acid, and sodium salicylate. Alongside questions relating to the dose-effect ratio, metabolisation, recovery, and diffusion of the substances to their site of action were investigated. The reproducibility of the procedure and its selectivity with regard to substances with a different mechanism of action is proven. The method allows classification of the substances according to their anti-inflammatory…

Cyclooxygenase inhibitors – current status and future prospects

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase and subsequent downstream synthetases. Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2. Both isoenzymes transform arachidonic acid to prostaglandins, but differ in their distribution and their physiological roles. Meanwhile, the responsible genes and their regulation have been clarified. COX-1, the pre-dominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow and platelet aggregation. In contrast, the inducible for…

Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor.

A novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids was synthesized to investigate the influence of different hydrogen-bond donor and acceptor groups at this specific position on the affinity to the glycine site of the NMDA receptor. These novel 3-indolylmethyl derivatives with ring-open (amines, sulfonamides, amides, ureas) and cyclic substituents (imidazolidin-2-ones, (thio)hydantoins) led to the discovery that compounds bearing a hydantoin substituent at the C-3 position of the indole nucleus are the most promising ones. In this series the hydantoins, ureas, and imidazolidin-2-ones were identified as very potent inhibitors of the binding of the glycine site specific l…

Regioisomeric 5(3)-aminomethyl-3(5)-phenylisoxazoles: synthesis, spectroscopic discrimination, and muscarinic activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens. Regioisomere 5(3)-Aminomethyl-3(5)-phenyl-isoxazole: Synthese, spektroskopische Unterscheidung und muskarinische Aktivitat Es werden verschiedene Verfahren zur regioselektiven Darstellung von 5(3)-Aminomethyl-3(5)-phenyl-isoxazolen beschrieben, die anhand ihrer spektroskopischen Daten, insbesondere der massenspektrosk…

Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow

The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of cycloxygenases COX-1 and COX-2. During recent years, combined 5-LOX/COX-inhibition, interfering with the biosynthesis of both prostaglandins and leukotrienes (LTs), has emerged as a possibility to avoid side effects related to COX-inhibition. The aim of the present study was to investigate if there is a contribution of mechanisms other than the reduction of inflammatory prostaglandins and leukotrienes to the anti-inflammatory effect of the LOX/COX inhibitor licofelone. In a flow chamber assay, licofelone (10-30 microM) dose-dependently decreased both the rolling and adhesion of leukocytes on …

ChemInform Abstract: Non-Steroidal Antiinflammatory Agents. Part 21. 2-Aryl-pyrrolo(2,1-b) benzothiazoles as Selective or Dual Inhibitors of Cyclooxygenase and 5- Lipoxygenase.

Nicht-medikamentöse Therapieverfahren

Ausgehend von der Vorstellung, dass ausere Faktoren die neuro-physiologischen Synchronisierungsvorgange mit beeinflussen und epileptische Anfalle triggern konnen, diskutiert man seit einigen Jahren vermehrt die Moglichkeit, diese externen Einflusse zu beeinflussen bzw. zu kontrollieren. Grundsatzlich bieten sich drei Therapieansatze an: 1) Relativ allgemein ist das Erkennen von typischen anfallsauslosenden Faktoren wie bestimmte Stresssituationen, deren Vermeidung sich durch eine Verhaltenstherapie unterstutzen lasst. 2) Die Desensitivierungstherapie basiert darauf, dass bestimmte externe Reize, wie Licht oder akustische Reize zu einer verstarkten Synchronisation fuhren. Appliziert man nun …

Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction.

The protooncogenes Ras and Raf play important roles in signal transduction pathways regulated by mitogen-activated protein kinases. Mutations of Ras that arrest the protein in its active state are frequently implicated in tumor formation. We used Ras and Raf proteins in the yeast two-hybrid system to search for natural or synthesized substances capable of modulating Ras/Raf interaction by specifically binding to one of the interacting partners. We found that cycloalkylidene carboxylic acids enhanced Ras/Raf interaction by acting on the cysteine-rich domain of Raf. Several analogues of the active substance 2-cyclohexylidene propanoic acid were synthesized and the importance of the semicyclic…

ChemInform Abstract: COX-2-Inhibitors: Present Level and Prospects

ChemInform Abstract: Investigations Concerning the COX/5-LOX Inhibiting and Hydroxyl Radical Scavenging Potencies of Novel 4,5-Diaryl Isoselenazoles.

The aim of this study was to investigate 4,5-diaryl isoselenazoles as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) which can intervene into the inflammatory processes via different mechanisms of action creating a new class of compounds. Here we describe the synthesis of COX/LOX inhibitors which additionally reduce the level of reactive oxygen species, such as hydroxyl radicals which are well known for supporting inflammation processes in Parkinson's disease, Alzheimer's disease and rheumatoid arthritis.

Investigations Concerning the Correlation of COX-1 Inhibitory and Hydroxyl Radical Scavenging Activity

The aim was to study the COX-1 inhibiting efficacy in context with hydroxyl radical scavenging properties of compounds bearing a carboxylic acid and ester function, respectively. In general, the acids are more potent radical scavengers than the corresponding esters but there is no clear correlation with their COX-1 inhibiting potencies. A feasible scavenging mechanism of carboxylic acids is discussed.

Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands

In our search for M2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M2-subtype selectivity.

Klinik der wichtigsten Erkrankungen unter besonderer Berücksichtigung der subjektiven und objektiven Symptome; Komplikationen, Prognose

Die Vielfalt der Symptomatologie epileptischer Anfalle ist durch das die epileptische Aktivitat generierende Hirnareal und die weitere Ausbreitung der epileptischen Erregung wahrend des Anfalls charakterisiert. Daruber hinaus ist die Symptomatologie auch von der syndromalen Entitat abhangig. Die Internationale Liga gegen Epilepsie hat zur Einordnung epileptischer Anfalle und epileptischer Syndrome zwei Klassifikationen geschaffen, um eine einheitliche Nomenklatur zu erreichen. Diese Nomenklatur bildet die Grundlage fur operationalisierte Diagnose- und Therapiekriterien.

ChemInform Abstract: NSAR: Classification and Pharmacological Effects

A novel class of potent nonglycosidic and nonpeptidic pan-selectin inhibitors.

An early step of the inflammatory response, the rolling of leukocytes on activated endothelial cells, is mediated by selectin/carbohydrate interactions. The tetrasaccharide sialy Lewisx is a ligand for E-, P-, and L-selectin and therefore serves as a lead structure for the development of analogues. A combination of synthesis and structure-based design allowed rapid optimization. The current lead 2a was evaluated in our E-selectin cell flow chamber assay where it proved to inhibit rolling and adhesion with an IC50 of 28+/-7 microM. The assays used are predictive for the in vivo efficacy of test compounds as shown for 2a in a proteose peptone induced peritonitis model of acute inflammation in…

Symptomatik der Anfälle

Elementar-motorische Anfalle werden vom primaren Motorkortex oder auch den supplementar-motorischen Arealen der kontralateralen Hemisphare generiert. In Abhangigkeit davon finden sich myoklone, tonische oder klonische Entauserungen, auch eine Minussymptomatik mit Paresen kann ein iktales Symptom darstellen. Dies ist abzugrenzen von einer postiktalen Lahmung (Todd-Parese), bei der das neurologische Defizit durch eine Untererregbarkeit des zuvor epileptisch aktiven Kortex bedingt ist und sich in der Regel in 1–2 Tagen wieder zuruckbildet. Eine postiktale Lahmung findet sich insbesondere in Zusammenhang mit Anfallen bei Hirnlasionen (z. B. nach einem Hirntumor oder einer zerebralen Ischamie). …

Moguntinones--new selective inhibitors for the treatment of human colorectal cancer.

Abstract 3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their pot…

Simultaneous determination of olanzapine, clozapine and demethylated metabolites in serum by on-line column-switching high-performance liquid chromatography.

An automated method for simultaneous routine quantification of the antipsychotic drugs clozapine, olanzapine and their demethylated metabolites is described. The method included adsorption on a cyanopropyl (CPS) coated clean-up column (10 microm; 10 x 2.0 mm I.D.), washing off interfering serum constituents to waste, and separation on C18 ODS Hypersil reversed phase material (5 microm; 250 x 4.6 mm I.D.) using acetonitrile-water-tetramethylethylenediamine (37:62.6:0.4, v/v/v) adjusted to pH 6.5 with concentrated acetic acid. UV-detection was performed at 254 nm. The limit of quantification was 10-20 ng/ml. Relative day to day standard variations ranged between 4.5 and 13.5%. The method is s…

Investigations concerning the COX/5-LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-diaryl isoselenazoles

The aim of this study was to investigate 4,5-diaryl isoselenazoles as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) which can intervene into the inflammatory processes via different mechanisms of action creating a new class of compounds. Here we describe the synthesis of COX/LOX inhibitors which additionally reduce the level of reactive oxygen species, such as hydroxyl radicals which are well known for supporting inflammation processes in Parkinson's disease, Alzheimer's disease and rheumatoid arthritis.

Non-steroidal Anti-inflammatory Agents, Part 24[1] Pyrrolidino Enaminones as Models to Mimic Arachidonic Acid

The pyrrolidino enaminones, with the carboxylic acid chain fixed at the nitrogen, inhibit cyclooxygenase more potently or selectively than 5-lipoxygenase. According to the structure-activity relationships discussed the potency depends significantly on the chain length of the carboxylic acid, the substitution pattern of the heterocyclic moiety and of the phenyl group. Compound 4c is the most efficient inhibitor of cyclooxygenase. For the binding profile the unfolded conformation of arachidonic acid and the energy-minimized conformations of flurbiprofen, diclofenac, ML 3000, and lead compound 4a were compared. In addition to known structural features, similar distances of the carboxylic acid …

Diaryl-dithiolanes and -isothiazoles: COX-1/COX-2 and 5-LOX-inhibitory, OH scavenging and anti-adhesive activities

Three series of non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting the cyclooxygenase/5-lipoxygenase (COX/5-LOX) pathways as such as formation of hydroxyl radicals and adhesion were prepared: 4,5-diaryl isothiazoles, 4,5-diaryl 3H-1,2-dithiole-3-thiones and 4,5-diaryl 3H-1,2-dithiole-3-ones. The aim of the present study was to develop substances which can intervene into the inflammatory processes via different mechanisms of action as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) with increased anti-inflammatory potential. The current lead 11a was evaluated in COX-1/2, 5-LOX and (*)OH scavenging in vitro assays and in a static adhesion assay where it proved to inhib…

Novel Insights and Therapeutical Applications in the Field of Inhibitors of COX-2

The discovery of the two isoenzymes COX-1 and COX-2 and the knowledge of their function, localisation and regulation has initiated the development of COX-2 selective inhibitors (coxibs). Inducible COX-2 at the peripheral site of inflammation has been detected in the early 1990s, the involvement of recently detected spinal COX-2 has led to new insights into mechanisms of pain and may explain analgesic and antipyretic properties of COX-2 selective inhibitors. The coxibs rofecoxib and celecoxib have been introduced into therapy and seem to offer some advantages over the classical non-selective NSAIDs. The search for new COX-2 inhibitors is going on, the development of etoricoxib and lumiracox…

Spectrofluorimetric Quantification of Malondialdehyde for Evaluation of Cyclooxygenase-1/Thromboxane Synthase Inhibition

The in vitro assay developed by Hartmann and Ledergerber (1995) utilizing the spectrofluorimetric quantification of malondialdehyde after reaction with thiobarbituric acid was modified and used for further investigations. The human whole blood was replaced by a platelet suspension of pig blood, and calcium ionophore A23187 was used instead of collagen for inducing the arachidonic acid cascade. The modified assay represents a simple, time and cost saving method for the evaluation of cyclooxygenase-1/thromboxane synthase inhibition. The reproducibility and comparability of results is given. Additional experiments allow classification of selective phospholipase A2, cyclooxygenase-1, and thromb…

Genetische Aspekte der Epilepsien

Bei den meisten der heute noch als idiopathisch oder genuin eingeordneten Epilepsien spielen vermutlich genetische Faktoren eine Rolle. So weisen Kinder von Eltern mit einer solchen Epilepsie ein Erkrankungsrisiko von ca. 7% auf, gegenuber der allgemeinen Pravalenz von 0,5-1% bezogen auf alle Epilepsien in der Bevolkerung. Bei Geschwistern ist das Risiko um das 2–3fache erhoht. Allerdings fallt unter die Epilepsien mit erblicher Komponente nur eine kleine Gruppe (ca. 2%) von uberwiegend kindlichen Epilepsien, fur die eine direkte monogene Vererbung belegt ist. Es handelt sich um zumeist autosomal-rezessiv vererbte Stoffwechselstorungen, Fehlbildungen oder mitochondrale Anomalien des Gehirns…

Diagnostik von ZNS-Erkrankungen mittels PET bzw. SPECT: Radiopharmazeutische Strategien und klinische Anwendungen

Radioaktiv markierte Molekule fur die nicht-invasive Darstellung biochemischer Funktionen haben seit etwa 25 Jahren betrachtlich zum Verstandnis normaler und gestorter Stoffwechselvorgange im Hirn beigetragen. In einigen Fallen hat dies dazu gefuhrt, dass 18F-markierte PET- bzw. 123I- und 99mTc-Radiodiagnostika ihren festen Platz bei der klinischen Diagnostik von Erkrankungen des Zentralen Nervensystems mittels der modernen tomographischen Techniken PET bzw. SPECT gefunden haben. Dies betrifft primar den Mb. Parkinson, die Epilepsie, zunehmend die Alzheimer Demenz, aber auch Hirntumore. Diese molekulare, neurochemische Diagnostik in vivo wird, in Konkurrenz zu etablierten klinischen Diagnos…

Vanillin Suppresses Metastatic Potential of Human Cancer Cells through PI3K Inhibition and Decreases Angiogenesis in Vivo

Vanillin, a food flavoring agent, has been shown to suppress cancer cell migration and metastasis in a mouse model, but its mechanism of action is unknown. In this report, we have examined the antimetastatic potential of vanillin and its structurally related compounds, vanillic acid, vanillyl alcohol, and apocynin on hepatocyte growth factor (HGF)-induced migration of human lung cancer cells by the Transwell assay. Vanillin and apocynin could inhibit cell migration, and both compounds selectively inhibited Akt phosphorylation of HGF signaling, without affecting phosphorylation of Met and Erk. Vanillin and apocynin could inhibit the enzymatic activity of phosphoinositide 3-kinase (PI3K), as …

Efficient synthesis and 5-LOX/COX-inhibitory activity of some 3-hydroxybenzo[b]thiophene-2-carboxylic acid derivatives

Abstract A series of 3-hydroxybenzo[ b ]thiophene-2-carboxylic acid derivatives has been prepared and subsequently evaluated with regards to the inhibition of 5-LOX/COX. Structure optimization furnished derivatives with promising in vitro activity as dual 5-LOX/COX inhibitors with submicromolar IC 50 values for inhibition of 5-LOX and COX-1, respectively.

1-Pyrrolines (3,4-Dihydro-2H-pyrroles) as a Template for New Drugs

3,4-Diarylmaleimides Effectively Inhibit Proliferation of FLT3-ITD-Positive Leukemic Cells, Induce Apoptosis and Show Additive Effects in Combination with Chemotherapeutic Drugs.

Abstract Internal tandem duplication (ITD) mutations of FLT3 are present in leukemic blasts of approximately 30% of AML patients. ITD-mutations of FLT3 confer a worse prognosis and decreased overall survival. Therefore, FLT3-tyrosine kinase is considered an attractive drug target in AML and several FLT3-tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials (CEP701, MLN518, Sorafenib, PKC412). However, using these drugs as monotherapy, against the setting of remarkable efficacy has emerged the problem of short duration of remission indicating rapid development of secondary resistance. In addition, up to 30% of patients may show primary resistance to currently availa…

Cyclooxygenase-1/2 (COX-1/COX-2) and 5-lipoxygenase (5-LOX) inhibitors of the 6,7-diaryl-2,3-1H-dihydropyrrolizine type

A series of 6,7-diaryl-2,3-1H-dihydropyrrolizines was prepared as COX-1/COX-2 and 5-LOX inhibitors. The inhibition of COX-1 was evaluated using intact bovine platelets as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of arachidonic metabolites was performed by HPLC for COX-1 and RIA for COX-2. The balance between COX-1/COX-2 and 5-LOX inhibition can be shifted by modifying the substitution pattern of the phenyl moiety at the 6- and 7-position of the pyrrolizine nucleus. Structure-activity relationships are discussed.

Antiepileptika – Wirkprinzipien und strukturelle Parameter. Wissenswertes zur Pharmakokinetik und Pharmakodynamik

Bereits im altesten bekannten Schrifttext der Menschheit, dem Gesetzeskodex von Hammurabi (1728 bis 1686 v. Chr.), wurde die Epilepsie erwahnt. In der Antike als “Heilige Krankheit” charakterisiert ist die Epilepsie die haufigste chronisch neurologische Erkrankung des zentralen Nervensystems. Nach aktuellen Schatzungen leiden etwa 0,4 bis 1 % der Bevolkerung an epileptischen Erkrankungen, wobei ein Drittel der Betroffenen meist junger ist als 16 Jahre.

ChemInform Abstract: The Pyrrole Moiety as a Template for COX-1/COX-2 Inhibitors.

Effect of Flavonol Derivatives on the Carrageenin-Induced Paw Edema in the Rat and Inhibition of Cyclooxygenase-1 and 5-Lipoxygenase in Vitro

Alkoxyflavonols were synthesized by the Algar-Flynn-Oyamada (AFO) cyclization of chalcones. Hydroxyflavonols were prepared by dealkylation of methoxyflavonols by refluxing in hydroiodic acid. The alkoxyflavonols 3-hydroxy-2-(2,3,4-trimethoxyphenyl)-4H-chromen-4-one (6), 2-(4-ethoxyphenyl)-3-hydroxy-4H-chromen-4-one (7), 2-(4-butoxyphenyl)-3-hydroxy-4H-chromen-4-one (10), and 2-(3-n-butoxyphenyl)-3-hydroxy-4H-chromen-4-one (11) as well as the trihydroxy derivative 3-hydroxy-2-(3,4,5-trihydroxyphenyl)-4H-chromen-4-one (18) displayed high anti-inflammatory activity in carrageenin-induced rat paw edema. Additionally, the inhibition of enzymes of the arachidonic acid cascade by the derivatives w…

Semiologische Klassifikation epileptischer Anfälle

Bemuhungen um eine Vereinfachung der derzeit gultigen Klassifikation einmal nach Anfallsformen und zum anderen nach epileptischen Syndromen gehen insbesondere von den epilepsiechirurgisch tatigen Epileptologen aus. Das Resultat ist die 1998 veroffentlichte semiologische Klassifikation epileptischer Anfalle, die eine syndromale Einheit von Symptomatik anstrebt. Sie soll als Diskussionsgrundlage fur die geplante Revision der IKEA dienen.

Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site.

Drugs used to treat various disorders target GABA A receptors. To develop alpha subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [(3)H]muscimol binding and in patch-clamp experiments with heterologously expressed GABA A alpha ibeta 3gamma 2 receptors (i = 1-6). The effects of 5-aminomethyl-3 H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all alpha subunit isoforms. 5-pipe…

Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists.

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H(1) receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for human histamine H(1) receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N-methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved sel…