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851.
Nadine Beetz Michael D. Harrison Marc Brede Xiangang Zong Michal J. Urbanski Anika Sietmann Jennifer Kaufling Stefan Lorkowski Michel Barrot Mathias W. Seeliger Maria Augusta Vieira-Coelho Pavel Hamet Daniel Gaudet Ondrej Seda Johanne Tremblay Theodore A. Kotchen Mary Kaldunski Rolf Nüsing Bela Szabo Howard J. Jacob Allen W. Cowley Jr. Martin Biel Monika Stoll Martin J. Lohse Ulrich Broeckel Lutz Hein 《The Journal of clinical investigation》2011,121(1):454
852.
Malcor JD Payrot N David M Faucon A Abouzid K Jacquot G Floquet N Debarbieux F Rougon G Martinez J Khrestchatisky M Vlieghe P Lisowski V 《Journal of medicinal chemistry》2012,55(5):2227-2241
Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments. 相似文献
853.
Certal V Halley F Virone-Oddos A Delorme C Karlsson A Rak A Thompson F Filoche-Rommé B El-Ahmad Y Carry JC Abecassis PY Lejeune P Vincent L Bonnevaux H Nicolas JP Bertrand T Marquette JP Michot N Benard T Below P Vade I Chatreaux F Lebourg G Pilorge F Angouillant-Boniface O Louboutin A Lengauer C Schio L 《Journal of medicinal chemistry》2012,55(10):4788-4805
Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts. 相似文献
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856.
Lennertz L Quednow BB Schuhmacher A Petrovsky N Frommann I Schulze-Rauschenbach S Landsberg MW Steinbrecher A Höfels S Pukrop R Klosterkötter J Franke PE Wölwer W Gaebel W Häfner H Maier W Wagner M Mössner R 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2012,15(9):1205-1215
Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development. 相似文献
857.
Mégarbané A Chouery E Mignon-Ravix C El Sabbagh S Corbani S Ghoch JA Jalkh N Mehawej C Lévy N Villard L 《American journal of medical genetics. Part A》2011,155(5):1147-1151
We report on two siblings with hypotonia, ambiguous genitalia, microcephaly, ptosis, microretrognathia, thin lips, seizures, absent ossification of pubic rami, and brain abnormalities at the MRI. The two siblings died at 5 and 8 months, respectively. Molecular analysis indicated that SOX9, ARX, and DHCR7 genes were normal. Comparative genomic hybridization (CGH)-array analysis performed on the younger boy indicated two notable deletions, one on paternally inherited chromosome 4, and one on maternally inherited chromosome 5. The same deletions were found in a normal sister. Differential diagnoses and the possibility of a hitherto unreported syndrome are discussed. 相似文献
858.
Jenetzky E Wijers CH Marcelis CM Zwink N Reutter H van Rooij IA 《American journal of medical genetics. Part A》2011,155(8):2039-41; author reply 2042-3
859.
Maija Haanpää Nadine Attal Miroslav BackonjaRalf Baron Michael BennettDidier Bouhassira Giorgio CruccuPer Hansson Jennifer A. HaythornthwaiteGian Domenico Iannetti Troels S. JensenTimo Kauppila Turo J. NurmikkoAndew S.C. Rice Michael RowbothamJordi Serra Claudia SommerBlair H. Smith Rolf-Detlef Treede 《Pain》2011,152(1):14-27
This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level.Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes.Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction.The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended. 相似文献
860.