68 results on '"Achim Kless"'
Search Results
2. Validity of the cold pressor test and pain sensitivity questionnaire via online self-administration.
- Author
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Matthew H McIntyre, andMe Research Team, Achim Kless, Peter Hein, Mark Field, and Joyce Y Tung
- Subjects
Medicine ,Science - Abstract
To determine the feasibility of complex home-based phenotyping, 1,876 research participants from the customer base of 23andMe completed an online version of a Pain Sensitivity Questionnaire (PSQ) as well as a cold pressor test (CPT) which is used in clinical assessments of pain. Overall our online version of the PSQ performed similarly to the original pen-and-paper version. Construct validity of the PSQ total was demonstrated by internal consistency and consistent discrimination between more and less painful items. Criterion validity was demonstrated by correlation with pain sensitivity as measured by the CPT. Within the same cohort we performed a cold pressor test using a layperson description and household equipment. Comparison with published reports from controlled studies revealed similar distributions of cold pain tolerance times (i.e., time elapsed before removing the hand from the water). Of those who elected to participate in the CPT, a large majority of participants did not report issues with the test procedure or noncompliance with the instructions (97%). We confirmed a large sex difference in CPT thresholds in line with published data, such that women removed their hands from the water at a median of 54.2 seconds, with men lasting for a median time of 82.7 seconds (Kruskal-Wallis statistic, p < 0.0001), but other factors like age or current pain treatment were at most weakly associated, and inconsistently between men and women. We introduce a new paradigm for performing pain testing, called testing@home, that, in the case of cold nociception, showed comparable results to studies conducted under controlled conditions and supervision of a health care professional.
- Published
- 2020
- Full Text
- View/download PDF
3. Genome-wide association study of pain sensitivity assessed by questionnaire and the cold pressor test
- Author
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Pierre, Fontanillas, Achim, Kless, John, Bothmer, and Joyce Y, Tung
- Subjects
Pain Threshold ,Anesthesiology and Pain Medicine ,Neurology ,Surveys and Questionnaires ,Humans ,Pain ,Female ,Neurology (clinical) ,Genome-Wide Association Study ,Pain Measurement - Abstract
We deployed an online pain sensitivity questionnaire (PSQ) and an at-home version of the cold pressor test (CPT) in a large genotyped cohort. We performed genome-wide association studies on the PSQ score (25,321 participants) and CPT duration (6853). We identified one new genome-wide significant locus associated with the PSQ score, which was located in the TSSC1 (also known as EIPR1 ) gene (rs58194899, OR = 0.950 [0.933-0.967], P -value = 1.9 × 10 -8 ). Although high pain sensitivity measured by both PSQ and CPT was associated with individual history of chronic and acute pains, genetic correlation analyses surprisingly suggested an opposite direction: PSQ score was inversely genetically correlated with neck and shoulder pain ( rg = -0.71), rheumatoid arthritis (-0.68), and osteoarthritis (-0.38), and with known risk factors, such as the length of working week (-0.65), smoking (-0.36), or extreme BMI (-0.23). Gene-based analysis followed by pathway analysis showed that genome-wide association studies results were enriched for genes expressed in the brain and involved in neuronal development and glutamatergic synapse signaling pathways. Finally, we confirmed that females with red hair were more sensitive to pain and found that genetic variation in the MC1R gene was associated with an increase in self-perceived pain sensitivity as assessed by the PSQ.
- Published
- 2021
4. Cytochrome P450 Classification of Drugs with Support Vector Machines Implementing the Nearest Point Algorithm.
- Author
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Achim Kless and Tatjana Eitrich
- Published
- 2004
- Full Text
- View/download PDF
5. A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP‐modulated NFAT signaling
- Author
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Mona L Knapp, Dalia Alansary, Vanessa Poth, Kathrin Förderer, Frederik Sommer, David Zimmer, Yvonne Schwarz, Nicolas Künzel, Achim Kless, Khaled Machaca, Volkhard Helms, Timo Mühlhaus, Michael Schroda, Annette Lis, and Barbara A Niemeyer
- Subjects
ORAI1 Protein ,Genetics ,Protein Isoforms ,Calcium ,Calcium Channels ,Calcium Signaling ,Stromal Interaction Molecule 1 ,Molecular Biology ,Biochemistry - Abstract
Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated Ca
- Published
- 2021
6. Classification of Highly Unbalanced CYP450 Data of Drugs Using Cost Sensitive Machine Learning Techniques.
- Author
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Tatjana Eitrich, Achim Kless, Claudia Druska, Wolfgang Meyer, and Johannes Grotendorst
- Published
- 2007
- Full Text
- View/download PDF
7. Structural Prediction of the Dimeric Form of the Mammalian Translocator Membrane Protein TSPO: A Key Target for Brain Diagnostics
- Author
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Juan Zeng, Riccardo Guareschi, Mangesh Damre, Ruyin Cao, Achim Kless, Bernd Neumaier, Andreas Bauer, Alejandro Giorgetti, Paolo Carloni, and Giulia Rossetti
- Subjects
TSPO ,radioligands ,PET ,oligomerization ,brain inflammation ,homology modeling ,molecular dynamics ,docking ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers—the suggested functional state of the protein—is limited to a solid-state nuclear magnetic resonance (NMR) study and to a model based on the previously-deposited solution NMR structure of the monomeric mouse protein. Computational studies performed here suggest that the NMR-solved structure in the presence of detergents is not prone to dimer formation and is furthermore unstable in its native membrane environment. We, therefore, propose a new model of the functionally-relevant dimeric form of the mouse protein, based on a prokaryotic homologue. The model, fully consistent with solid-state NMR data, is very different from the previous predictions. Hence, it provides, for the first time, structural insights into this pharmaceutically-important target which are fully consistent with experimental data.
- Published
- 2018
- Full Text
- View/download PDF
8. Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.
- Author
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Xiaojing Cong, Pablo Campomanes, Achim Kless, Inga Schapitz, Markus Wagener, Thomas Koch, and Paolo Carloni
- Subjects
Medicine ,Science - Abstract
Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.
- Published
- 2015
- Full Text
- View/download PDF
9. Validity of the Cold Pressor Test and Pain Sensitivity Questionnaire via online self-administration
- Author
-
Matthew H McIntyre, 23andMe Research Team, Achim Kless, Peter Hein, Mark Field, and Joyce Y Tung
- Subjects
Questionnaires ,Male ,Physiology ,Sensory Physiology ,Social Sciences ,Hands ,Controlled studies ,Pathology and Laboratory Medicine ,0302 clinical medicine ,030202 anesthesiology ,Surveys and Questionnaires ,Internal consistency ,Medicine and Health Sciences ,Psychology ,Computer Networks ,Musculoskeletal System ,Statistic ,Pain Measurement ,Sex Characteristics ,Multidisciplinary ,Pharmaceutics ,Cold pressor test ,Middle Aged ,Sensory Systems ,Cold Temperature ,Arms ,Nociception ,Somatosensory System ,Research Design ,Neuropathic pain ,Cohort ,Medicine ,Female ,Anatomy ,Self-administration ,Research Article ,Adult ,Pain Threshold ,Computer and Information Sciences ,medicine.medical_specialty ,Psychometrics ,Science ,Lower Back Pain ,Pain ,Research and Analysis Methods ,03 medical and health sciences ,Young Adult ,Signs and Symptoms ,Sex Factors ,Drug Therapy ,Diagnostic Medicine ,Threshold of pain ,medicine ,Criterion validity ,Humans ,Neuropathic Pain ,Aged ,Internet ,Survey Research ,business.industry ,Biology and Life Sciences ,Pain Sensation ,Construct validity ,Body Limbs ,Physical therapy ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
To determine the feasibility of complex home-based phenotyping, 1,876 research participants from the customer base of 23andMe participated in an online version of a Pain Sensitivity Questionnaire (PSQ) as well as a cold pressor test (CPT) which is used in clinical assessments of pain. Overall our online version of the PSQ performed similarly to the original pen-and-paper version. Construct validity of the PSQ total was demonstrated by internal consistency and consistent discrimination between more and less painful items. Criterion validity was demonstrated by correlation with pain sensitivity as measured by the cold pressor test. Within the same cohort we performed a cold pressor test using a layperson description and household equipment. Comparison with published reports from controlled studies revealed similar distributions of cold pain tolerance times (i.e., time elapsed before removing the hand from the water). Of those who elected to participate in the CPT, a large majority of participants did not report issues with the test procedure or noncompliance to the instructions (97%). We confirmed a large sex difference in CPT thresholds in line with published data, such that women removed their hands from the water at a median of 54.2 seconds, with men lasting for a median time of 82.7 seconds (Kruskal-Wallis statistic, p < 0.0001), but other factors like age or current pain treatment were at most weakly associated, and inconsistently between men and women. We introduce a new paradigm for performing pain testing, called testing@home, that, in the case of cold nociception, showed comparable results to studies conducted under controlled conditions and supervision of a health care professional.SummaryResearch paradigms employing home-based phenotyping are feasible, with both questionnaires and self-administration of a well-established experimental human pain model yielding similar results compared to controlled settings.
- Published
- 2019
10. Genome-wide association study of pain sensitivity assessed by questionnaire and the cold pressor test
- Author
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Joyce Y. Tung, Achim Kless, Fontanillas P, and Bothmer J
- Subjects
medicine.medical_specialty ,biology ,business.industry ,Chronic pain ,Cold pressor test ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Genome-wide association study ,Locus (genetics) ,medicine.disease ,Genetic architecture ,ComputingMilieux_GENERAL ,Thyroid peroxidase ,ComputerSystemsOrganization_MISCELLANEOUS ,Internal medicine ,Genetic variation ,Cohort ,biology.protein ,medicine ,business - Abstract
Altered pain sensitivity is believed to play an important role in the development of chronic pain, a common debilitating condition affecting an estimated 1 in 5 adults. Pain sensitivity varies broadly between individuals, and it is notoriously difficult to measure at scale in large populations. Although pain sensitivity is known to be moderately heritable, only a small number of genetic studies have been published and they have had limited success in identifying the genetic architecture of pain sensitivity. In this study, we deployed an online pain sensitivity questionnaire (PSQ) and an at-home version of the cold pressor test (CPT) in a large genotyped cohort. We performed genome-wide association studies (GWAS) on the PSQ score (n = 25,321) and CPT duration (n = 6,853). Despite a reasonably large sample size, we identified only one genome-wide significant locus associated with the PSQ score, which was located in the TSSC1 gene (rs58194899, OR = 0.950 [0.933-0.967], P-value = 1.9*10−8). This gene is responsible for intracellular cell trafficking and it could modulate pain sensitivity via changes in neuroplasticity. PSQ score is genetically correlated with chronic and acute pain, including chronic neck and shoulder pain (rg = 0.71), fracture (0.71), rheumatoid arthritis (0.68), osteoarthritis (0.38), and pneumothorax (0.82). PSQ score was also genetically correlated with known risk factors, such as the length of working week (0.65), noisy workplace (0.41), smoking (0.36), or extreme BMI (0.23). Gene-based analysis followed by pathway analysis showed that GWAS results were enriched for genes expressed in the brain, predominantly in the frontal cortex and basal ganglia, and enriched for genes involved in neuronal development and glutamatergic synapse signaling pathways. Finally, we confirmed that females with red hair were more sensitive to pain and found that genetic variation in the MC1R gene was associated with an increase in pain sensitivity as assessed by the PSQ. Overall, we detailed the genetic background of pain sensitivity using scalable at-home procedures that may serve as a blueprint for larger genetic studies.Author SummaryDespite decades of research and many advances in our understanding of the physical, emotional, and psychological aspects, the genetic contribution to pain sensitivity is still largely unknown. We administered a pain sensitivity questionnaire in parallel with an experimental cold pressor test in a large, genotyped cohort of 31,000 research participants, and found a novel genome-wide genetic association in TSSC1. This gene is responsible for intracellular cell trafficking and it could modulate pain sensitivity via changes in neuroplasticity. Overall, the pain sensitivity measurements revealed strong positive genetic correlations with chronic and acute pain conditions, as well as with unhealthy traits and behaviors, such as obesity, smoking, or difficult working conditions. The genetic association results also suggested, perhaps unsurprisingly, that only the brain tissues could be relevant for pain sensitivity, and identified enrichments for glutamatergic synapse pathways. Despite the complexity of pain sensitivity, our study demonstrated that it is now possible to deploy sophisticated pain questionnaires online and perform experimental medicine tests in at-home settings to further study the genetic architecture of pain sensitivity.
- Published
- 2019
11. Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors
- Author
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Astrid S. Obrecht, Günther Schmalzing, Michael Schaefer, Anni Röse, Achim Kless, Jannis E. Meents, Ralf Hausmann, Aliaa Abdelrahman, Nicole Urban, Angelika Lampert, and Christa E. Müller
- Subjects
0301 basic medicine ,Patch-Clamp Techniques ,Purinergic P2X Receptor Antagonists ,Voltage clamp ,Allosteric regulation ,Xenopus ,Pharmacology ,Neurotransmission ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,Xenopus laevis ,0302 clinical medicine ,Allosteric Regulation ,Ganglia, Spinal ,Aurintricarboxylic acid ,medicine ,Animals ,Humans ,Receptor ,Neurons ,biology ,Aurintricarboxylic Acid ,Antagonist ,biology.organism_classification ,High-Throughput Screening Assays ,Rats ,Molecular Docking Simulation ,Receptors, Purinergic P2X1 ,030104 developmental biology ,Mechanism of action ,chemistry ,Oocytes ,medicine.symptom ,030217 neurology & neurosurgery ,Allosteric Site ,Receptors, Purinergic P2X3 - Abstract
The homotrimeric P2X3 receptor, one of the seven members of the ATP-gated P2X receptor family, plays a crucial role in sensory neurotransmission. P2X3 receptor antagonists have been identified as promising drugs to treat chronic cough and are suggested to offer pain relief in chronic pain such as neuropathic pain. Here, we analysed whether compounds affect P2X3 receptor activity by high-throughput screening of the Spectrum Collection of 2000 approved drugs, natural products and bioactive substances. We identified aurintricarboxylic acid (ATA) as a nanomolar-potency antagonist of P2X3 receptor-mediated responses. Two-electrode voltage clamp electrophysiology-based concentration–response analysis and selectivity profiling revealed that ATA strongly inhibits the rP2X1 and rP2X3 receptors (with IC50 values of 8.6 nM and 72.9 nM, respectively) and more weakly inhibits P2X2/3, P2X2, P2X4 or P2X7 receptors (IC50 values of 0.76 μM, 22 μM, 763 μM or 118 μM, respectively). Patch-clamp analysis of mouse DRG neurons revealed that ATA inhibited native P2X3 and P2X2/3 receptors to a similar extent than rat P2X3 and P2X2/3 receptors expressed in Xenopus oocytes. In a radioligand binding assay, up to 30 μM ATA did not compete with [3H]-ATP for rP2X3 receptor binding, indicating a non-competitive mechanism of action. Molecular docking studies, site-directed mutagenesis and concentration–response analysis revealed that ATA binds to the negative allosteric site of the hP2X3 receptor. In summary, ATA as a drug-like pharmacological tool compound is a nanomolar-potency, allosteric antagonist with selectivity towards αβ-methylene-ATP-sensitive P2X1 and P2X3 receptors.
- Published
- 2019
12. Investigating targets for neuropharmacological intervention by molecular dynamics simulations
- Author
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Paolo Carloni, Luhua Lai, Giulia Rossetti, Achim Kless, and Tiago F. Outeiro
- Subjects
Drug ,Disease onset ,media_common.quotation_subject ,Molecular Dynamics Simulation ,Diagnostic tools ,Biochemistry ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Intervention (counseling) ,Drug Discovery ,Medicine ,Humans ,Physiological saline ,030304 developmental biology ,media_common ,0303 health sciences ,business.industry ,Neurodegenerative Diseases ,Medical research ,3. Good health ,Neuroprotective Agents ,business ,Neuroscience ,030217 neurology & neurosurgery ,Simulation methods - Abstract
Medical research has identified over 500 brain disorders. Among these, there are still only very few neuropathologies whose causes are fully understood and, consequently, very few drugs whose mechanism of action is known. No FDA drug has been identified for major neurodegenerative diseases, such as Alzheimer's and Parkinson's. We still lack effective treatments and strategies for modulating progression or even early neurodegenerative disease onset diagnostic tools. A great support toward the highly needed identification of neuroactive drugs comes from computer simulation methods and, in particular, from molecular dynamics (MD). This provides insight into structure–function relationship of a target and predicts structure, dynamics and energetics of ligand/target complexes under biologically relevant conditions like temperature and physiological saline concentration. Here, we present examples of the predictive power of MD for neuroactive ligands/target complexes. This brief survey from our own research shows the usefulness of partnerships between academia and industry, and from joint efforts between experimental and theoretical groups.
- Published
- 2019
13. Structural Prediction of the Dimeric Form of the Mammalian Translocator Membrane Protein TSPO: A Key Target for Brain Diagnostics
- Author
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Alejandro Giorgetti, Bernd Neumaier, Ruyin Cao, Giulia Rossetti, Andreas Bauer, Mangesh V. Damre, Achim Kless, Riccardo Guareschi, Paolo Carloni, and Juan Zeng
- Subjects
0301 basic medicine ,Dimer ,homology modeling ,Mouse Protein ,Ligands ,01 natural sciences ,Catalysis ,Article ,oligomerization ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,Molecular dynamics ,chemistry.chemical_compound ,Receptors, GABA ,radioligands ,0103 physical sciences ,Animals ,Homology modeling ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,brain inflammation ,Binding Sites ,010304 chemical physics ,Chemistry ,Organic Chemistry ,General Medicine ,Nmr data ,molecular dynamics ,Computer Science Applications ,Molecular Docking Simulation ,030104 developmental biology ,Membrane ,PET ,Cholesterol ,lcsh:Biology (General) ,lcsh:QD1-999 ,Membrane protein ,Docking (molecular) ,Positron-Emission Tomography ,ddc:540 ,docking ,Biophysics ,TSPO ,Protein Multimerization ,Protein Binding - Abstract
Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers&mdash, the suggested functional state of the protein&mdash, is limited to a solid-state nuclear magnetic resonance (NMR) study and to a model based on the previously-deposited solution NMR structure of the monomeric mouse protein. Computational studies performed here suggest that the NMR-solved structure in the presence of detergents is not prone to dimer formation and is furthermore unstable in its native membrane environment. We, therefore, propose a new model of the functionally-relevant dimeric form of the mouse protein, based on a prokaryotic homologue. The model, fully consistent with solid-state NMR data, is very different from the previous predictions. Hence, it provides, for the first time, structural insights into this pharmaceutically-important target which are fully consistent with experimental data.
- Published
- 2018
- Full Text
- View/download PDF
14. Role of the Cytoplasmatic M3-M4 Loop for the Homopentameric Assembly of a Chimeric Nicotinic Alpha 7 Receptor
- Author
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Heike Lauks, Lena Hauswirth, Jonas Deppe, Achim Kless, Ralf Hausmann, and Guenther Schmalzing
- Subjects
Loop (topology) ,Nicotinic agonist ,Chemistry ,Biophysics ,Alpha (ethology) ,Receptor ,Cell biology - Published
- 2019
15. Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
- Author
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Ralf Hausmann, Günther Schmalzing, and Achim Kless
- Subjects
Models, Molecular ,Ion flow ,Protein Conformation ,Computational biology ,P2X quaternary structure ,Biochemistry ,Article ,Protein structure ,Complementary DNA ,Drug Discovery ,mutational P2X receptor analysis ,P2X assembly domains ,Animals ,Humans ,Binding site ,P2X receptor function ,Receptor ,Zebrafish ,Ion channel ,P2X ATP binding pocket ,Pharmacology ,Binding Sites ,biology ,Organic Chemistry ,biology.organism_classification ,Structure and function ,Receptors, Purinergic P2X ,Mutagenesis, Site-Directed ,Molecular Medicine - Abstract
P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-A crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures.
- Published
- 2015
16. Localization of the gate and selectivity filter of the full-length P2X7 receptor
- Author
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Anja Pippel, Fritz Markwardt, Ronja Woltersdorf, Michaela Stolz, Günther Schmalzing, and Achim Kless
- Subjects
0301 basic medicine ,Models, Molecular ,Protein Conformation ,Protein subunit ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Protein structure ,Adenosine Triphosphate ,Cysteine ,Receptor ,Multidisciplinary ,Chemistry ,Hydrogen bond ,Hydrogen Bonding ,Carbocyanines ,Transmembrane protein ,Transport protein ,Transmembrane domain ,Protein Transport ,030104 developmental biology ,PNAS Plus ,Amino Acid Substitution ,Covalent bond ,Biophysics ,Receptors, Purinergic P2X7 ,Ion Channel Gating ,030217 neurology & neurosurgery - Abstract
The P2X7 receptor (P2X7R) belongs to the P2X family of ATP-gated cation channels. P2X7Rs are expressed in epithelial cells, leukocytes, and microglia, and they play important roles in immunological and inflammatory processes. P2X7Rs are obligate homotrimers, with each subunit having two transmembrane helices, TM1 and TM2. Structural and functional data regarding the P2X2 and P2X4 receptors indicate that the central trihelical TM2 bundle forms the intrinsic transmembrane channel of P2X receptors. Here, we studied the accessibility of single cysteines substituted along the pre-TM2 and TM2 helix (residues 327-357) of the P2X7R using as readouts (i) the covalent maleimide fluorescence accessibility of the surface-bound P2X7R and (ii) covalent modulation of macroscopic and single-channel currents using extracellularly and intracellularly applied methanethiosulfonate (MTS) reagents. We found that the channel opening extends from the pre-TM2 region through the outer half of the trihelical TM2 channel. Covalently adducted MTS ethylammonium+ (MTSEA+) strongly increased the probability that the channel was open by delaying channel closing of seven of eight responsive human P2X7R (hP2X7R) mutants. Structural modeling, as supported by experimental probing, suggested that resulting intraluminal hydrogen bonding interactions stabilize the open-channel state. The additional decrease in single-channel conductance by MTSEA+ in five of seven positions identified Y336, S339, L341C, Y343, and G345 as the narrowest part of the channel lumen. The gate and ion-selectivity filter of the P2X7R could be colocalized at and around residue S342. None of our results provided any evidence for dilation of the hP2X7R channel on sustained stimulation with ATP4.
- Published
- 2017
17. Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
- Author
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Klaus Linz, Olaf Will, André Welbers, Virginia Marossek, Rolf Terlinden, Klaus Hansen, Bert Nolte, Irena Loryan, Margareta Hammarlund-Udenaes, Paul Ratcliffe, Achim Kless, Anita Wegert, Derek Saunders, Edmund Hoppe, Felix Held, and Publica
- Subjects
Male ,0301 basic medicine ,Chemistry, Pharmaceutical ,intracellular concentration ,Pharmaceutical Science ,Diamines ,Pharmacology ,Lipidoses ,Models, Biological ,030226 pharmacology & pharmacy ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Drug Discovery ,Animals ,Humans ,Distribution (pharmacology) ,Tissue Distribution ,Rats, Wistar ,unbound drug ,Lung ,Phospholipids ,Phospholipidosis ,Chemistry ,Brain ,Extracellular Fluid ,Hep G2 Cells ,In vitro ,Rats ,brain slice ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,drug induced phospholipidosis ,Models, Chemical ,Drug development ,Biochemistry ,Models, Animal ,Drug delivery ,Molecular Medicine ,Female ,lipids (amino acids, peptides, and proteins) ,Lysosomes ,pharmacokinetics ,Intracellular ,lung slice - Abstract
Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.
- Published
- 2017
18. Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol
- Author
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Sven Frormann, B.Y. Kögel, Bernd Sundermann, Klaus Linz, Achim Kless, Helmut Sonnenschein, Wolfgang P. Schröder, Stefan Schunk, Werner Englberger, Derek Saunders, Hans Schick, Tieno Germann, Saskia Zemolka, Thomas Christoph, Claudia Hinze, Stefan Oberbörsch, and Stephanie Harlfinger
- Subjects
Indole test ,business.industry ,Cebranopadol ,Organic Chemistry ,NOP ,Analgesic ,Pharmacology ,Biochemistry ,In vitro ,Nociception ,In vivo ,Drug Discovery ,Neuropathic pain ,Medicine ,business - Abstract
In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.
- Published
- 2014
19. Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists
- Author
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Tieno Germann, Bernd Sundermann, Sven Frormann, Helmut Sonnenschein, Hans Schick, Werner Englberger, B.Y. Kögel, Derek Saunders, Achim Kless, Klaus Linz, Stefan Oberbörsch, Stephanie Harlfinger, Saskia Zemolka, Thomas Christoph, Claudia Hinze, Wolfgang P. Schröder, and Stefan Schunk
- Subjects
Indole test ,chemistry.chemical_classification ,Stereochemistry ,medicine.drug_class ,Organic Chemistry ,NOP ,Peptide ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Nociceptin receptor ,chemistry ,Opioid receptor ,Drug Discovery ,Tryptophol ,medicine ,Receptor ,Opioid peptide - Abstract
We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.
- Published
- 2014
20. Thiol dependent intramolecular locking of Orai1 channels
- Author
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Barbara Schmidt, Kathrin Dörr, Heiko Rieger, Achim Kless, Barbara A. Niemeyer, Dalia Alansary, and Ivan Bogeski
- Subjects
0301 basic medicine ,ORAI1 Protein ,Protein subunit ,Plasma protein binding ,Article ,Serine ,03 medical and health sciences ,Humans ,Stromal Interaction Molecule 1 ,Sulfhydryl Compounds ,Mesylates ,Multidisciplinary ,030102 biochemistry & molecular biology ,ORAI1 ,Chemistry ,HEK 293 cells ,STIM1 ,Neoplasm Proteins ,Protein Subunits ,Transmembrane domain ,HEK293 Cells ,030104 developmental biology ,Biochemistry ,Mutation ,Biophysics ,Reactive Oxygen Species ,Oxidation-Reduction ,Protein Binding ,Cysteine - Abstract
Store-operated Ca2+ entry mediated by STIM1-gated Orai1 channels is essential to activate immune cells and its inhibition or gain-of-function can lead to immune dysfunction and other pathologies. Reactive oxygen species interacting with cysteine residues can alter protein function. Pretreatment of the Ca2+ selective Orai1 with the oxidant H2O2 reduces ICRAC with C195, distant to the pore, being its major redox sensor. However, the mechanism of inhibition remained elusive. Here we combine experimental and theoretical approaches and show that oxidation of Orai1 leads to reduced subunit interaction, slows diffusion and that either oxidized C195 or its oxidomimetic mutation C195D located at the exit of transmembrane helix 3 virtually eliminates channel activation by intramolecular interaction with S239 of transmembrane helix 4, thereby locking the channel in a closed conformation. Our results demonstrate a novel mechanistic model for ROS-mediated inhibition of Orai1 and identify a candidate residue for pharmaceutical intervention.
- Published
- 2016
21. Salt Bridge Switching from Arg290/Glu167 to Arg290/ATP Promotes the Closed-to-Open Transition of the P2X2 Receptor
- Author
-
Fritz Markwardt, Matthias U. Kassack, Ralf Hausmann, Günther Schmalzing, Achim Kless, Gregor Bahrenberg, Daniel Kuhlmann, and Janka Günther
- Subjects
Models, Molecular ,Patch-Clamp Techniques ,Purinergic P2X Receptor Antagonists ,Stereochemistry ,Static Electricity ,Glutamic Acid ,Ionic bonding ,Arginine ,Purinergic P2X Receptor Agonists ,Xenopus laevis ,Adenosine Triphosphate ,Static electricity ,Side chain ,Animals ,Peptide bond ,Homology modeling ,Receptor ,Pharmacology ,Binding Sites ,Chemistry ,Recombinant Proteins ,Rats ,Mutation ,Mutagenesis, Site-Directed ,Oocytes ,Molecular Medicine ,Female ,Salt bridge ,Signal transduction ,Ion Channel Gating ,Receptors, Purinergic P2X4 ,Receptors, Purinergic P2X2 - Abstract
P2X receptors are trimeric adenosine-5'-triphosphate (ATP)-gated cation channels involved in fast signal transduction in many cell types. In this study, we used homology modeling of the rat P2X2 receptor with the zebrafish P2X4 X-ray template to determine that the side chains of the Glu167 and Arg290 residues are in close spatial vicinity within the ATP-binding pocket when the rat P2X2 channel is closed. Through charge reversal mutation analysis and mutant cycle analysis, we obtained evidence that Glu167 and Arg290 form an electrostatic interaction. In addition, disulfide trapping indicated the close proximity of Glu167 and Arg290 when the channel is in the closed state, but not in the ATP-bound open state. Consistent with a gating-induced movement that disrupts the Glu167/Arg290 salt bridge, a comparison of the closed and open rat P2X2 receptor models revealed a significant rearrangement of the protein backbone and the side chains of the Glu167 and Arg290 residues during the closed-to-open transition. The associated release of the Glu167/Arg290 salt bridge during channel opening allows a strong ionic interaction between Arg290 and a γ-phosphate oxygen of ATP. We conclude from these results that the state-dependent salt bridge switching from Arg290/Glu167 to Arg290/ATP fulfills a dual role: to destabilize the closed state of the receptor and to promote the ionic coordination of ATP in the ATP-binding pocket.
- Published
- 2012
22. Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules
- Author
-
Nils Damann, Torsten Hertrampf, Antonio Nardi, and Achim Kless
- Subjects
Pharmacology ,Binding Sites ,Drug discovery ,Chemistry ,Sodium channel ,Organic Chemistry ,Subtype selectivity ,Voltage-Gated Sodium Channels ,Biochemistry ,Small molecule ,Drug Discovery ,Humans ,Protein Isoforms ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Neuroscience ,Ion channel ,Sodium Channel Inhibitors ,Sodium Channel Blockers - Abstract
Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.
- Published
- 2012
23. Role of the Left Flipper Domain in the Homotrimeric Assembly and Function of P2X Receptors
- Author
-
Fritz Markwardt, Günther Schmalzing, Angela Hein, Ralf Hausmann, and Achim Kless
- Subjects
Physics ,Biophysics ,Function (mathematics) ,Flipper ,Receptor ,Domain (software engineering) ,Cell biology - Published
- 2018
24. Role of G338 of the Second Transmembrane Domain in Gating of the Human P2X7 Receptor
- Author
-
Guenther Schmalzing, Fritz Markwardt, Achim Kless, Nancy Zipfel, Anja Pippel, and Michaela Stolz
- Subjects
Agonist ,biology ,Chemistry ,medicine.drug_class ,Biophysics ,Xenopus ,Gating ,biology.organism_classification ,Transmembrane domain ,Biochemistry ,medicine ,Ligand-gated ion channel ,Reversal potential ,Receptor ,Ion channel - Abstract
The human P2X7 receptor (hP2X7R) is an ATP-gated nonspecific cation channel. It is expressed in cells of the immune system. Via this receptor, ATP, released during cell damage or hypoxia, serves as danger associated molecular pattern to induce inflammatory reactions. In comparison to other P2X receptors, P2X7R-dependent ionic currents differ in their activation kinetics by an absence of desensitization and induction of large membrane pores by long lasting agonist applications, i.e. the gating and permeation mechanisms of P2X7 receptors are not fully understood.G338 within the second transmembrane domain (TM2) is part of the narrow ion channel pore domain. Substitution of G338 to cysteine reversed the gating behaviour of the hP2X7R channel, i.e. hP2X7G338C expressing Xenopus oocytes displayed a leak conductance which is decreased by application of ATP or by the P2X7R agonist, BzATP. Substitution of extracellular Na+ by the larger organic Tris+ significantly decreased the ion conductance and shifted the reversal potential of the ATP-induced current to more negative potentials indicating that the leak current was carried by cations.Modeling the structural changes of hP2X7G338C during ATP application with the recently published truncated zebrafish P2X4 receptor model as template we found that G338 is located at the narrowest part of the closed ion channel pore and substitution by cysteine pushes the TM2 of the three subunits apart leading to an incomplete channel closure. ATP application leads to a conformation switch of hP2X7G338C which allows an interaction of C338 with Y40 and Y343 decreasing the ion channel pore diameter and leading to a reduced ion current.These findings point to a critical role of G338 in gating the P2X7 receptor.This work was supported by the German research foundation (DFG, Ma 1581/15-1, Schm 536/9-1
- Published
- 2016
25. Mit Data Mining Entwicklungsprozesse beschleunigen
- Author
-
Matthias Pförtner, Axel Schunk, Achim Kless, Alexei Tarkhov, Thomas Engel, and Ivan P. Bangov
- Subjects
General Chemical Engineering ,General Chemistry - Abstract
Das Pharmaunternehmen Grunenthal, eine Forschergruppe am Computer-Chemie-Centrum Erlangen und der Softwareentwickler Molecular Networks haben gemeinsam neue Verfahren zur Datenanalyse in der Pharmaforschung entwickelt. Eine Zwischenbilanz.
- Published
- 2003
26. Construction of chiral Ti(IV)–Rh(I)–salenophos complexes and their application in the asymmetric hydroformylation of functionalised olefins
- Author
-
Achim Kless, Michael Quirmbach, Vitali I. Tararov, Jens Holz, and Armin Börner
- Subjects
chemistry.chemical_classification ,Organic Chemistry ,chemistry.chemical_element ,Aldehyde ,Catalysis ,Rhodium ,Inorganic Chemistry ,Metal ,chemistry.chemical_compound ,chemistry ,visual_art ,Reagent ,Polymer chemistry ,Vinyl acetate ,visual_art.visual_art_medium ,Organic chemistry ,Physical and Theoretical Chemistry ,Hydroformylation ,Phosphine ,Coordination geometry - Abstract
The synthesis of new chiral salenophos-type ligands bearing `hard' and `soft' coordination sites is described. The polyfunctionalised ligands are used for the construction of monometallic and early–late heterobimetallic complexes. In the reaction with titanium(IV) reagents the salen subunit selectively coordinated to the `hard' metal. The phosphine groups in turn can be coordinated to rhodium(I). The coordination geometry of the diphosphine–Rh subunit is strongly influenced by the counter ligands COD or CO and Cl, respectively. In the asymmetric hydroformylation of vinyl acetate with one of the Rh–Ti-complexes, the branched aldehyde is predominantly formed with 30% ee.
- Published
- 1999
27. Retro-cycloadditions and sigmatropic shifts: the C7H8 and C7 H10 potential energy surfaces
- Author
-
J. Tian, Maja Nendel, Brett R. Beno, Achim Kless, Sarah Wilsey, and K. N. Houk
- Subjects
chemistry.chemical_compound ,Bicyclic molecule ,Chemistry ,Computational chemistry ,General Chemical Engineering ,Density functional theory ,Field theory (psychology) ,General Chemistry ,Complete active space ,Self consistent ,Sigmatropic reaction ,Potential energy ,Norbornene - Abstract
Retro-cycloadditions and thermal rearrangements of hydrocarbons have been investigated with density functional theory (B3LYP) and complete active space multiconfiguration self consistent field theory (CASSCF and CASPT2). We review recent results from our laboratories. Subjects are the laser-induced retro-Diels- Alder reactions of norbornene, thermal retro-Diels-Alder reactions of norbornenes and isopropylidenorbornene, 1,3-sigmatropic shifts of vinylcyclopropane and bicyclo(3.2.0)heptenes, and the 1,5-sigmatropic shifts of norcaradienes. The competition between concerted and stepwise processes and the nature of diradicals formed in these processes are described.
- Published
- 1998
28. Studies on the formation of uniform η3-coordinated triphos-Mo(0)-complexes
- Author
-
Helmut Reinke, Achim Kless, Armin Börner, and Jens Holz
- Subjects
Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Stereochemistry ,Organic Chemistry ,Materials Chemistry ,Molecule ,Chelation ,Physical and Theoretical Chemistry ,Ring (chemistry) ,Biochemistry ,Triphos - Abstract
A comparative study on the reaction of (CO)3Mo(CH3CN)3 with a series of homologous chiral and prochiral trisphosphines is presented. Only one of the tripodal ligands formed the desired unique complex (CO)3Mo(η3-triphos) (3b) being the first example of a Mo(0)-complex containing a seven- as well as an eight-membered chelate ring. Spectroscopic properties of this complex and two different η2-coordinated species are discussed. The molecular structure of the η3-coordinated complex 3b has been determined by X-ray crystallography.
- Published
- 1998
29. Ab Initio Studies of Rhodium(I)−N-Alkenylamide Complexes with cis- and trans-Coordinating Phosphines: Relevance for the Mechanism of Catalytic Asymmetric Hydrogenation of Prochiral Dehydroamino Acids
- Author
-
Detlef Heller, Rüdiger Selke, Armin Börner, and Achim Kless
- Subjects
Stereochemistry ,Organic Chemistry ,Imine ,Asymmetric hydrogenation ,chemistry.chemical_element ,Tautomer ,Catalysis ,Rhodium ,Enamine ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Intramolecular force ,Physical and Theoretical Chemistry ,Cis–trans isomerism - Abstract
A theoretical study on cationic Rh(I)−N-alkenylamide complexes is presented, which are important intermediates in the asymmetric hydrogenation affording N-acylamino acids. The assumption of different intermediates investigated is based on the inter- and intramolecular equilibrium of diastereomeric complexes in the hydrogenation mechanism. The geometry optimizations were performed at the MP2 level of theory using relativistic pseudopotentials for rhodium, followed by QCISD(T) single-point calculations. The intermediates containing cis- or trans-coordinated phosphines have been compared structurally and energetically, and the influence of solvents is discussed. In the equilibrium consisting of uncoordinated substrate and substrate complexes, all tautomeric complexes were found in the calculation and have a minimum on the potential hypersurface. However, the occurrence of enamine/imine and amide/imine-ol tautomers could be excluded for the catalytic reaction, because they implement irreversible steps (C−H ac...
- Published
- 1997
30. Heteromeric assembly of P2X subunits
- Author
-
Anika, Saul, Ralf, Hausmann, Achim, Kless, and Annette, Nicke
- Subjects
homomer ,ligand binding site ,P2XR ,subunit interface ,heteromer ,Review Article ,Neuroscience ,clustering - Abstract
Transcripts and/or proteins of P2X receptor (P2XR) subunits have been found in virtually all mammalian tissues. Generally more than one of the seven known P2X subunits have been identified in a given cell type. Six of the seven cloned P2X subunits can efficiently form functional homotrimeric ion channels in recombinant expression systems. This is in contrast to other ligand-gated ion channel families, such as the Cys-loop or glutamate receptors, where homomeric assemblies seem to represent the exception rather than the rule. P2XR mediated responses recorded from native tissues rarely match exactly the biophysical and pharmacological properties of heterologously expressed homomeric P2XRs. Heterotrimerization of P2X subunits is likely to account for this observed diversity. While the existence of heterotrimeric P2X2/3Rs and their role in physiological processes is well established, the composition of most other P2XR heteromers and/or the interplay between distinct trimeric receptor complexes in native tissues is not clear. After a description of P2XR assembly and the structure of the intersubunit ATP-binding site, this review summarizes the distribution of P2XR subunits in selected mammalian cell types and the biochemically and/or functionally characterized heteromeric P2XRs that have been observed upon heterologous co-expression of P2XR subunits. We further provide examples where the postulated heteromeric P2XRs have been suggested to occur in native tissues and an overview of the currently available pharmacological tools that have been used to discriminate between homo- and heteromeric P2XRs.
- Published
- 2013
31. The first chiral early-late heterobimetallic complex — A titanium(IV)-palladium(II) complex based on salenophos
- Author
-
Achim Kless, Wolfgang Baumann, Jens Holz, Rhett Kempe, Anke Spannenberg, C. Lefeber, and Armin Börner
- Subjects
Ligand ,Stereochemistry ,Organic Chemistry ,chemistry.chemical_element ,Nuclear magnetic resonance spectroscopy ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Polymer chemistry ,Chelation ,Phosphine ,Titanium ,Palladium ,A titanium - Abstract
The synthesis of the chiral polyfunctional diphosphine salenophos 1 is described. The new ligand bearing hard and soft coordination sites chelates titanium(IV) as well as palladium(II) in a defined manner provided a certain order during the introduction of the two metals was kept. In this way the first chiral early-late heterobimetallic complex could be synthesized. It was fully characterized by NMR spectroscopy and X-ray structural analysis. Remarkable features of the heterobimetallic complex are the trans coordination of the phosphine groups on palladium and the distance between Ti and Pd which is more than 4.13 A.
- Published
- 1996
32. Chiral phosphinephosphites having axial and central chirality in asymmetric hydroformylations
- Author
-
Renat Kadyrov, Rüdiger Selke, Jens Holz, Christine Fischer, Detlef Heller, Armin Börner, and Achim Kless
- Subjects
Stereochemistry ,organic chemicals ,Organic Chemistry ,chemistry.chemical_element ,Catalysis ,Rhodium ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Axial chirality ,Allyl acetate ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Chirality (chemistry) ,Hydroformylation - Abstract
Chiral phosphinephosphites were prepared by the reaction of enantiomerically pure cis - or trans -3-diphenylphosphinotetrahydrofuran-4-ol with atropisomeric chlorophosphites. These ligands were tested in the rhodium catalyzed hydroformylation of allyl acetate. Selectivities up to 44% ee were observed in dependence on the configuration of the applied phosphinephosphites and the bulk of the aromatic groups bound to the phosphorus. The results clearly show that both, central and axial chirality are responsible for the stereochemical outcome of this reaction.
- Published
- 1996
33. ChemInform Abstract: Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules
- Author
-
Antonio Nardi, Torsten Hertrampf, Nils Damann, and Achim Kless
- Subjects
Chemistry ,Drug discovery ,Sodium channel ,General Medicine ,Neuroscience ,Small molecule ,Sodium Channel Inhibitors - Abstract
Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.
- Published
- 2012
34. Hydroxyalkylphosphines in asymmetric hydrogenations
- Author
-
Stephan Trinkhaus, Rüdiger Selke, Armin Börner, Susanne Borns, Achim Kless, Detlef Heller, and Jens Holz
- Subjects
Ligand ,Organic Chemistry ,Asymmetric hydrogenation ,Acetal ,chemistry.chemical_element ,Medicinal chemistry ,Catalysis ,Rhodium ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,Methanol ,Itaconic acid ,Physical and Theoretical Chemistry ,Methylene - Abstract
The synthesis of chiral bisphosphines bearing a hydroxyl group in a rigid backbone is described. These compounds which are analogues of the prominent ligand DIOP formed definite rhodium complexes. IR spectra provided evidence that the hydroxyl groups do not participate in the complexation to the metal or to one of the acetal oxygen atoms. The complexes have proven successful in the asymmetric hydrogenation of prochiral functionalized olefins in different solvents. In methanol only small effects could be detected in comparison to parent complexes which do not carry a hydroxyl group. However, when hydrogenations were performed in methylene chloride or toluene significant differences in the enantioselectivities (by up to 17 %ee) were observed, especially in the reaction with itaconic acid or its dimethyl ester, respectively. In the latter cases the effect is contingent on the spatial orientation of the hydroxyl group in the catalyst.
- Published
- 1995
35. β‐Alkoxy‐ and β‐Hydroxyalkylphosphanes as Ligands in the Stereoselective Hydrogenation — A Comparison
- Author
-
Jens Holz, Detlef Heller, Achim Kless, Rhett Kempe, Wolfgang Baumann, and Armin Börner
- Subjects
Stereochemistry ,Asymmetric hydrogenation ,chemistry.chemical_element ,Ether ,Oxygen ,Rhodium ,Inorganic Chemistry ,Metal ,chemistry.chemical_compound ,chemistry ,visual_art ,Alkoxy group ,visual_art.visual_art_medium ,Stereoselectivity - Abstract
Optically pure 1,4-bis(diphenylphosphanyl)-2-hydroxy-butane (2) and its methyl ether 1 can be conveniently prepared by starting from chiral pool substances such as malic or L-ascorbic acid. Different pathways to these compounds were elucidated. In one case an interesting migration of an acetalic OH-protective group was observed. The reaction of the bisphosphanes with Rh1 or PdII gave uniform metal complexes. On the basis of X-ray structural analysis, NMR and IR data it was concluded that in the investigated precatalysts of the type [Rh(COD)(bisphosphane)]BF4 a coordination of the alkoxy or hydroxy oxygen to the metal does not take place. Nevertheless, significant differences in enantioselectivity and activity could be observed when several prochiral substrates were hydrogenated.
- Published
- 1995
36. Zur Komplexierung von enantiomerenreinen cis- und trans-3-Diphenylphosphino-4-hydroxy-tetrahydrofuranen mit [Rh(COD)2]BF4
- Author
-
Armin Börner, Annegret Tillack, Renat Kadyrov, Jens Holz, Achim Kless, and Wolfgang Baumann
- Subjects
Stereochemistry ,Organic Chemistry ,Intermolecular force ,Infrared spectroscopy ,chemistry.chemical_element ,Alcohol ,Biochemistry ,Medicinal chemistry ,Rhodium ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Group (periodic table) ,Materials Chemistry ,Physical and Theoretical Chemistry ,Phosphine - Abstract
The complexation behaviour of cis- und trans-3-diphenylphosphino-4-hydroxyl-tetrahydrofurans with [Rh(COD)2]BF4 is studied with the help of NMR and IR spectroscopy. In dependence of the spatial arrangement of hydroxyl and phosphino group the formation of different intra- and intermolecular bridged O-P complexes has been observed.
- Published
- 1995
37. Synthesis of an optically active hydroxy diphosphine, a new ligand for asymmetric catalysis
- Author
-
Jens Holz, Achim Kless, Detlef Heller, Ulrich Berens, and Armin Börner
- Subjects
Stereochemistry ,Chemistry ,Ligand ,Organic Chemistry ,Drug Discovery ,Enantioselective synthesis ,Optically active ,Biochemistry - Abstract
The synthesis of (4R,5R)-4,5-bis(diphenylphosphinomethyl)-2-hydroxymethyl-2-phenyl-1,3-dioxolane 1 which is related to DIOP is described. The application of this new ligand in asymmetric catalysis is illustrated in the stereodifferentiating hydrogenation.
- Published
- 1994
38. ChemInform Abstract: Synthesis of an Optically Active Hydroxy Diphosphine, a New Ligand for Asymmetric Catalysis
- Author
-
Achim Kless, Armin Boerner, Ulrich Berens, J. Holz, and Detlef Heller
- Subjects
Chemistry ,Ligand ,Enantioselective synthesis ,General Medicine ,Optically active ,Combinatorial chemistry - Published
- 2010
39. ChemInform Abstract: Hydroxyalkylphosphines in Asymmetric Hydrogenations
- Author
-
Armin Boerner, Stephan Trinkhaus, Rüdiger Selke, Achim Kless, Detlef Heller, J. Holz, and Susanne Borns
- Subjects
Chemistry ,Organic chemistry ,General Medicine - Published
- 2010
40. ChemInform Abstract: Chiral Phosphinephosphites Having Axial and Central Chirality in Asymmetric Hydroformylations
- Author
-
Renat Kadyrov, Detlef Heller, Achim Kless, R. Selke, Armin Boerner, J. Holz, and Christine Fischer
- Subjects
Chemical physics ,Chemistry ,General Medicine ,Chirality (chemistry) - Published
- 2010
41. ChemInform Abstract: An Efficient Strategy for the Synthesis of New Chiral and Prochiral Trisphosphines
- Author
-
Armin Boerner, Achim Kless, and J. Holz
- Subjects
Stereochemistry ,Chemistry ,General Medicine ,Combinatorial chemistry - Published
- 2010
42. ChemInform Abstract: The First Chiral Early-Late Heterobimetallic Complex - A Titanium(IV)- Palladium(II) Complex Based on Salenophos
- Author
-
Armin Boerner, Achim Kless, Rhett Kempe, and Anke Spannenberg, J. Holz, C. Lefeber, and Wolfgang Baumann
- Subjects
chemistry ,Polymer chemistry ,chemistry.chemical_element ,General Medicine ,Palladium ,A titanium - Published
- 2010
43. ChemInform Abstract: Retro-Cycloadditions and Sigmatropic Shifts: The C7H8 and C7H10 Potential Energy Surfaces
- Author
-
Sarah Wilsey, Jing Tian, K. N. Houk, Brett R. Beno, Achim Kless, and Maja Nendel
- Subjects
Computational chemistry ,Chemistry ,Stereochemistry ,General Medicine ,Sigmatropic reaction ,Potential energy - Published
- 2010
44. ChemInform Abstract: Construction of Chiral Ti(IV)-Rh(I)-Salenophos Complexes and Their Application in the Asymmetric Hydroformylation of Functionalized Olefins
- Author
-
Armin Boerner, Jens Holz, Achim Kless, Vitali I. Tararov, and Michael Quirmbach
- Subjects
Chemistry ,Polymer chemistry ,General Medicine ,Hydroformylation - Published
- 2010
45. Classification of Highly Unbalanced CYP450 Data of Drugs Using Cost Sensitive Machine Learning Techniques
- Author
-
Johannes Grotendorst, Wolfgang Meyer, Tatjana Eitrich, Achim Kless, and Claudia Druska
- Subjects
Databases, Factual ,Active learning (machine learning) ,Computer science ,General Chemical Engineering ,Drug Evaluation, Preclinical ,Linear classifier ,Feature selection ,Semi-supervised learning ,Library and Information Sciences ,Machine learning ,computer.software_genre ,Relevance vector machine ,Cytochrome P-450 Enzyme System ,Artificial Intelligence ,Oversampling ,Throughput (business) ,Structured support vector machine ,Chemistry ,business.industry ,Online machine learning ,General Chemistry ,General Medicine ,Class (biology) ,Computer Science Applications ,Data set ,ComputingMethodologies_PATTERNRECOGNITION ,Computational learning theory ,Pharmaceutical Preparations ,Cheminformatics ,Test set ,Costs and Cost Analysis ,Key (cryptography) ,Data mining ,Artificial intelligence ,business ,computer ,Algorithms - Abstract
In this paper, we study the classifications of unbalanced data sets of drugs. As an example we chose a data set of 2D6 inhibitors of cytochrome P450. The human cytochrome P450 2D6 isoform plays a key role in the metabolism of many drugs in the preclinical drug discovery process. We have collected a data set from annotated public data and calculated physicochemical properties with chemoinformatics methods. On top of this data, we have built classifiers based on machine learning methods. Data sets with different class distributions lead to the effect that conventional machine learning methods are biased toward the larger class. To overcome this problem and to obtain sensitive but also accurate classifiers we combine machine learning and feature selection methods with techniques addressing the problem of unbalanced classification, such as oversampling and threshold moving. We have used our own implementation of a support vector machine algorithm as well as the maximum entropy method. Our feature selection is based on the unsupervised McCabe method. The classification results from our test set are compared structurally with compounds from the training set. We show that the applied algorithms enable the effective high throughput in silico classification of potential drug candidates.
- Published
- 2007
46. An Efficient Strategy for the Synthesis of New Chiral and Prochiral Trisphosphines
- Author
-
Armin Börner, Achim Kless, and Jens Holz
- Subjects
Chemistry ,Organic Chemistry ,Combinatorial chemistry - Published
- 1996
47. Cytochrome P450 Classification of Drugs with Support Vector Machines Implementing the Nearest Point Algorithm
- Author
-
Tatjana Eitrich and Achim Kless
- Subjects
Engineering ,business.industry ,Supervised learning ,Pattern recognition ,Feature selection ,Machine learning ,computer.software_genre ,Class (biology) ,Support vector machine ,Data set ,ComputingMethodologies_PATTERNRECOGNITION ,Kernel method ,Cheminformatics ,Test set ,Artificial intelligence ,business ,computer ,Algorithm - Abstract
Cytochrome P450s are an important class of drug metabolizing enzymes which play a significant role in drug metabolism, and thus in the drug discovery process. With a data set that was compiled from public available data on cytochrome P450 drug interaction data, and derived calculated chemoinformatics data, we have built binary classifiers based on kernel methods, in particular support vector machines implementing the nearest point algorithm. Feature selection is used as a preliminary stage of supervised learning. We work on supervised as well as on unsupervised selection methods. The classification results from a selected subset of the test set are compared structurally with compounds from the training set.
- Published
- 2004
48. Corrigendum: Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules
- Author
-
Nils Damann, Antonio Nardi, Torsten Hertrampf, and Achim Kless
- Subjects
Pharmacology ,Chemistry ,Sodium channel ,Organic Chemistry ,Drug Discovery ,Biophysics ,Molecular Medicine ,Subtype selectivity ,General Pharmacology, Toxicology and Pharmaceutics ,Biochemistry ,Small molecule ,Ion channel - Published
- 2012
49. Origin of the Preference for the Orbital Symmetry Forbidden Stereochemistry of the 1,5-Sigmatropic Shift of Substituted Norcaradienes
- Author
-
Maja Nendel, Sarah Wilsey, Achim Kless, and K. N. Houk
- Subjects
Colloid and Surface Chemistry ,Chemistry ,Computational chemistry ,Stereochemistry ,General Chemistry ,Symmetry (geometry) ,Sigmatropic reaction ,Biochemistry ,Catalysis ,Preference - Published
- 1999
50. A new chiral multidentate ligand for asymmetric catalysis
- Author
-
Renat Kadyrov, Henri B. Kagan, Jens Holz, Armin Börner, and Achim Kless
- Subjects
Denticity ,Ligand ,Stereochemistry ,Organic Chemistry ,Chiral ligand ,Enantioselective synthesis ,Biochemistry ,Combinatorial chemistry ,Metal ,chemistry.chemical_compound ,chemistry ,visual_art ,Drug Discovery ,visual_art.visual_art_medium ,Bifunctional - Abstract
The synthesis of enantiomerically pure ( R,R )-N,N′-bis(3-diphenylphosphino-2-hydroxybenzylidene)-1,2-diphenyl-1,2-ethanediamine ( 1 ) is described. This multidentate salentype ligand offers several possibilities for the construction of chiral mono-nuclear or bi-nuclear metal complexes, which may be useful in bifunctional asymmetric catalysis.
- Published
- 1995
Catalog
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