Suzuki N

References (17)

Title : Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554 - Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
Author(s) : Maezaki H , Tawada M , Yamashita T , Banno Y , Miyamoto Y , Yamamoto Y , Ikedo K , Kosaka T , Tsubotani S , Tani A , Asakawa T , Suzuki N , Oi S
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :3565 , 2017
Abstract : We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1' pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.
ESTHER : Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
PubMedSearch : Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
PubMedID: 28579121

Title : Quality of life in purely ocular myasthenia in Japan - Suzuki_2014_BMC.Neurol_14_142
Author(s) : Suzuki S , Murai H , Imai T , Nagane Y , Masuda M , Tsuda E , Konno S , Oji S , Nakane S , Motomura M , Suzuki N , Utsugisawa K
Ref : BMC Neurol , 14 :142 , 2014
Abstract : BACKGROUND: Since there has been no conclusive evidence regarding the treatment of ocular myasthenia, treatment guidelines were recently issued by the European Federation of Neurological Societies/European Neurological Society (EFNS/ENS). However, the therapeutic outcomes concerning the quality-of-life (QOL) of patients with ocular myasthenia are not yet fully understood.
METHODS: We investigated the therapeutic outcomes of patients with purely ocular myasthenia in a multicenter cross-sectional survey in Japan. To evaluate the severity of ocular symptoms, we used the ocular-quantitative MG (QMG) score advocated by Myasthenia Gravis Foundation of America. We used the Japanese translated version of the MG-QOL15, a self-appraised scoring system.
RESULTS: Of 607 myasthenia gravis (MG) patients with an observation-duration of illness >= 2 years, the cases of 123 patients (20%) were limited to ocular muscles (purely ocular myasthenia). During the entire clinical course, 81 patients experienced both ptosis and diplopia, 36 had ptosis alone, and six had diplopia alone. Acetyl-cholinesterase inhibitors and prednisolone were used in 98 and 52 patients, respectively. Treatment improved ocular symptoms, with the mean reduction in ocular-QMG score of 2.3 +/- 1.8 points. However, 47 patients (38%) failed to gain minimal manifestation or a better status. Patients with unfavorable outcomes also self-reported severe QOL impairment. Multivariate analyses showed that the pretreatment ocular-QMG score was associated with unfavorable outcomes, but not associated with the patient's QOL. CONCLUSION: A treatment strategy designed in accord with a patient's ocular presentation must be considered in order to improve ocular symptoms and the patient's QOL.
ESTHER : Suzuki_2014_BMC.Neurol_14_142
PubMedSearch : Suzuki_2014_BMC.Neurol_14_142
PubMedID: 24996227

Title : Topical naphazoline in the treatment of myasthenic blepharoptosis - Nagane_2011_Muscle.Nerve_44_41
Author(s) : Nagane Y , Utsugisawa K , Suzuki S , Masuda M , Shimizu Y , Utsumi H , Uchiyama S , Suzuki N
Ref : Muscle & Nerve , 44 :41 , 2011
Abstract : INTRODUCTION: When treating ocular myasthenia gravis (MG), the risk/benefit profile of corticosteroids is unclear, and acetylcholinesterase inhibitors are not very effective. We examined the efficacy of topical naphazoline in the treatment of myasthenic blepharoptosis. METHODS: Sixty MG patients with blepharoptosis (32 with ocular symptoms only and 28 with mild generalized symptoms) were enrolled in a multicenter open trial of topical naphazoline. The effects were reported by patients via a questionnaire and were also confirmed for each patient at the clinic. RESULTS: Among 70 eyes of 60 patients, 20 eyes (28.6%) of 17 patients (28.3%) exhibited a marked response (full eye opening), and 24 eyes (34.3%) of 20 patients (33.3%) showed a good response (adequate but incomplete eye opening). Topical naphazoline was evaluated as useful in the treatment of myasthenic blepharoptosis by >70% of the patients. CONCLUSIONS: Topical naphazoline was found to be an effective supplementary symptomatic treatment for myasthenic blepharoptosis.
ESTHER : Nagane_2011_Muscle.Nerve_44_41
PubMedSearch : Nagane_2011_Muscle.Nerve_44_41
PubMedID: 21491460

Title : Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor - Miyamoto_2011_J.Med.Chem_54_831
Author(s) : Miyamoto Y , Banno Y , Yamashita T , Fujimoto T , Oi S , Moritoh Y , Asakawa T , Kataoka O , Yashiro H , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Sasaki M , Funami M , Amano M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Journal of Medicinal Chemistry , 54 :831 , 2011
Abstract : Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]ac etic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.
ESTHER : Miyamoto_2011_J.Med.Chem_54_831
PubMedSearch : Miyamoto_2011_J.Med.Chem_54_831
PubMedID: 21218817
Gene_locus related to this paper: human-DPP4

Title : Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125 - Miyamoto_2011_Bioorg.Med.Chem_19_172
Author(s) : Miyamoto Y , Banno Y , Yamashita T , Fujimoto T , Oi S , Moritoh Y , Asakawa T , Kataoka O , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Funami M , Amano M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Bioorganic & Medicinal Chemistry , 19 :172 , 2011
Abstract : We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]ac etyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.
ESTHER : Miyamoto_2011_Bioorg.Med.Chem_19_172
PubMedSearch : Miyamoto_2011_Bioorg.Med.Chem_19_172
PubMedID: 21163664

Title : Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: a new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554 - Banno_2011_Bioorg.Med.Chem_19_4953
Author(s) : Banno Y , Miyamoto Y , Sasaki M , Oi S , Asakawa T , Kataoka O , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Funami M , Tawada M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Bioorganic & Medicinal Chemistry , 19 :4953 , 2011
Abstract : The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)o xy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.
ESTHER : Banno_2011_Bioorg.Med.Chem_19_4953
PubMedSearch : Banno_2011_Bioorg.Med.Chem_19_4953
PubMedID: 21764322
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554 - Maezaki_2011_Bioorg.Med.Chem_19_4482
Author(s) : Maezaki H , Banno Y , Miyamoto Y , Moritoh Y , Asakawa T , Kataoka O , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Sasaki M , Tsubotani S , Tani A , Funami M , Yamamoto Y , Tawada M , Aertgeerts K , Yano J , Oi S
Ref : Bioorganic & Medicinal Chemistry , 19 :4482 , 2011
Abstract : Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine- 2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC(5)(0)=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
ESTHER : Maezaki_2011_Bioorg.Med.Chem_19_4482
PubMedSearch : Maezaki_2011_Bioorg.Med.Chem_19_4482
PubMedID: 21741847
Gene_locus related to this paper: human-DPP4

Title : A novel dipeptidyl peptidase-4 inhibitor, alogliptin (SYR-322), is effective in diabetic rats with sulfonylurea-induced secondary failure - Asakawa_2009_Life.Sci_85_122
Author(s) : Asakawa T , Moritoh Y , Kataoka O , Suzuki N , Takeuchi K , Odaka H
Ref : Life Sciences , 85 :122 , 2009
Abstract : AIMS: Loss of efficacy over time or secondary failure occurs somewhat often and remains a major concern of sulfonylurea (SU) therapy. In this study, we investigated the benefits of alogliptin, an oral, potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in a rat model exhibiting SU secondary failure. MAIN METHODS: Neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), a non-obese model of type 2 diabetes, were used in these studies. The effects of alogliptin on DPP-4 activity and glucagon-like peptide 1 (GLP-1) concentration were determined by measuring their levels in plasma. In addition, the effects of alogliptin on an oral glucose tolerance test were investigated by using an SU secondary failure model. KEY FINDINGS: Alogliptin dose dependently suppressed plasma DPP-4 activity leading to an increase in the plasma active form of GLP-1 and improved glucose excursion in N-STZ-1.5 rats. Repeated administration of glibenclamide resulted in unresponsiveness or loss of glucose tolerance typical of secondary failure. In these rats, alogliptin exhibited significant improvement of glucose excursion with significant increase in insulin secretion. By contrast, glibenclamide and nateglinide had no effect on the glucose tolerance of these rats. SIGNIFICANCE: The above findings suggest that alogliptin was effective at improving glucose tolerance and therefore overcoming SU induced secondary failure in N-STZ-1.5 rats.
ESTHER : Asakawa_2009_Life.Sci_85_122
PubMedSearch : Asakawa_2009_Life.Sci_85_122
PubMedID: 19427871

Title : Comparative analysis of the Corynebacterium glutamicum group and complete genome sequence of strain R - Yukawa_2007_Microbiology_153_1042
Author(s) : Yukawa H , Omumasaba CA , Nonaka H , Kos P , Okai N , Suzuki N , Suda M , Tsuge Y , Watanabe J , Ikeda Y , Vertes AA , Inui M
Ref : Microbiology , 153 :1042 , 2007
Abstract : The complete genome sequence of Corynebacterium glutamicum strain R was determined to allow its comparative analysis with other corynebacteria. The biology of corynebacteria was explored by refining the definition of the subset of genes that constitutes the corynebacterial core as well as those characteristic of saprophytic and pathogenic ecological niches. In addition, the relative scarcity of corynebacterial sigma factors and the plasticity of their two-component system machinery reflect their relatively exacting nutritional requirements and reduced membrane-associated and secreted proteins. The conservation of key genes and pathways between corynebacteria, mycobacteria and Nocardia validates the use of C. glutamicum to study fundamental processes that are conserved in slow-growing mycobacteria, including pathogenesis-associated mechanisms. The discovery of 39 novel genes in C. glutamicum R that have not been previously reported in other corynebacteria supports the rationale for sequencing additional corynebacterial genomes to better define the corynebacterial pan-genome and identify previously undetected metabolic pathways in these organisms.
ESTHER : Yukawa_2007_Microbiology_153_1042
PubMedSearch : Yukawa_2007_Microbiology_153_1042
PubMedID: 17379713
Gene_locus related to this paper: corgb-a4qhr7 , corgb-a4qhw6 , corgl-199 , corgl-CGL0007 , corgl-CGL0081 , corgl-CGL0340 , corgl-CGL0343 , corgl-CGL0591 , corgl-CGL1031 , corgl-Cgl1133 , corgl-CGL1144 , corgl-CGL1481 , corgl-CGL2002 , corgl-CGL2067 , corgl-CGL2181 , corgl-Cgl2249 , corgl-CGL2254 , corgl-CGL2393 , corgl-CGL2474 , corgl-CGL2878 , corgl-ephli , corgl-metx , corgl-q8nlr5 , corgl-q8nlz1 , corgl-y967 , corgt-g6wsn6

Title : Isolation and characterization of a native composite transposon, Tn14751, carrying 17.4 kilobases of Corynebacterium glutamicum chromosomal DNA - Inui_2005_Appl.Environ.Microbiol_71_407
Author(s) : Inui M , Tsuge Y , Suzuki N , Vertes AA , Yukawa H
Ref : Applied Environmental Microbiology , 71 :407 , 2005
Abstract : A native composite transposon was isolated from Corynebacterium glutamicum ATCC 14751. This transposon comprises two functional copies of a corynebacterial IS31831-like insertion sequence organized as converging terminal inverted repeats. This novel 20.3-kb element, Tn14751, carries 17.4 kb of C. glutamicum chromosomal DNA containing various genes, including genes involved in purine biosynthesis but not genes related to bacterial warfare, such as genes encoding mediators of antibiotic resistance or extracellular toxins. A derivative of this element carrying a kanamycin resistance cassette, minicomposite Tn14751, transposed into the genome of C. glutamicum at an efficiency of 1.8 x 10(2) transformants per mug of DNA. Random insertion of the Tn14751 derivative carrying the kanamycin resistance cassette into the chromosome was verified by Southern hybridization. This work paves the way for realization of the concept of minimum genome factories in the search for metabolic engineering via genome-scale directed evolution through a combination of random and directed approaches.
ESTHER : Inui_2005_Appl.Environ.Microbiol_71_407
PubMedSearch : Inui_2005_Appl.Environ.Microbiol_71_407
PubMedID: 15640215
Gene_locus related to this paper: corgl-CGL2596

Title : Large-scale engineering of the Corynebacterium glutamicum genome - Suzuki_2005_Appl.Environ.Microbiol_71_3369
Author(s) : Suzuki N , Okayama S , Nonaka H , Tsuge Y , Inui M , Yukawa H
Ref : Applied Environmental Microbiology , 71 :3369 , 2005
Abstract : The engineering of Corynebacterium glutamicum is important for enhanced production of biochemicals. To construct an improved C. glutamicum genome, we developed a precise genome excision method based on the Cre/loxP recombination system and successfully deleted 11 distinct genomic regions identified by comparative analysis of C. glutamicum genomes. Despite the loss of several predicted open reading frames, the mutant cells exhibited normal growth under standard laboratory conditions. With a total of 250 kb (7.5% of the genome), the 11 genomic regions were loaded with cryptic prophages, transposons, and genes of unknown function which were dispensable for cell growth, indicating recent horizontal acquisitions to the genome. This provides an interesting background for functional genomic studies and can be used in the improvement of cell traits.
ESTHER : Suzuki_2005_Appl.Environ.Microbiol_71_3369
PubMedSearch : Suzuki_2005_Appl.Environ.Microbiol_71_3369
PubMedID: 15933044
Gene_locus related to this paper: corgl-q5krb4

Title : Regulation of cerebral microcirculation--update - Tomita_2000_Keio.J.Med_49_26
Author(s) : Tomita M , Suzuki N , Hamel E , Busija D , Lauritzen M
Ref : Keio J Med , 49 :26 , 2000
Abstract : The present symposium during Brain 99 was convened to explore the current aspects of the neural (extrinsic and intrinsic) and chemical control of the microvasculature in the brain with specific relevance to stimuli and rapid flow responses. N. Suzuki demonstrated the presence of neurokinin-1 receptors along the axons of vasoactive intestinal polypeptide-containing cerebrovascular parasympathetic nerves. Since the receptors were activated by substance P, calcitonin gene-related peptide and neurokinin released from coexisting sensory nerve fibers, the parasympathetic (vasodilating) fibers could effect rapid local flow increases. N. Suzuki, however, considered this as part of an elaborate defensive network protecting the brain from invasions by noxious substances. E. Hamel discussed the responses of the microvessels to neurotransmitters and suggested that nitric oxide (NO) released from intrinsic neurons may serve as a relay in the flow activation responses by intracerebral cholinergic fibers originating in the basal forebrain nuclei. D. Busija summarized a vasodilating system of activated N-methyl-D-asparate receptors located on neurons involving Ca influx-NO production, and activated ATP-sensitive potassium channels located in the vascular system. According to Busija, such interactions were disrupted during hypoxia and ischemia due to cyclooxygenase-derived superoxide anion. M. Lauritzen observed a 10 times larger increase in blood flow on stimulation of the climbing nerve as compared with that following the parallel nerve stimulation. The former transmitters are considered by him to be NO and K, and the latter NO and adenosine. Each speaker singled out NO as a common mediator for the microvasculature in the rapid local flow increases.
ESTHER : Tomita_2000_Keio.J.Med_49_26
PubMedSearch : Tomita_2000_Keio.J.Med_49_26
PubMedID: 10750378

Title : A detailed linkage map of medaka, Oryzias latipes: comparative genomics and genome evolution - Naruse_2000_Genetics_154_1773
Author(s) : Naruse K , Fukamachi S , Mitani H , Kondo M , Matsuoka T , Kondo S , Hanamura N , Morita Y , Hasegawa K , Nishigaki R , Shimada A , Wada H , Kusakabe T , Suzuki N , Kinoshita M , Kanamori A , Terado T , Kimura H , Nonaka M , Shima A
Ref : Genetics , 154 :1773 , 2000
Abstract : We mapped 633 markers (488 AFLPs, 28 RAPDs, 34 IRSs, 75 ESTs, 4 STSs, and 4 phenotypic markers) for the Medaka Oryzias latipes, a teleost fish of the order Beloniformes. Linkage was determined using a reference typing DNA panel from 39 cell lines derived from backcross progeny. This panel provided unlimited DNA for the accumulation of mapping data. The total map length of Medaka was 1354.5 cM and 24 linkage groups were detected, corresponding to the haploid chromosome number of the organism. Thirteen to 49 markers for each linkage group were obtained. Conserved synteny between Medaka and zebrafish was observed for 2 independent linkage groups. Unlike zebrafish, however, the Medaka linkage map showed obvious restriction of recombination on the linkage group containing the male-determining region (Y) locus compared to the autosomal chromosomes.
ESTHER : Naruse_2000_Genetics_154_1773
PubMedSearch : Naruse_2000_Genetics_154_1773
PubMedID: 10747068

Title : Congenital euthyroid goitre with impaired thyroglobulin transport - Ohyama_1994_Clin.Endocrinol.(Oxf)_41_129
Author(s) : Ohyama Y , Hosoya T , Kameya T , Suzuki N , Nakamura S , Kazahari K , Shibayama K , Yokota Y , Matsuura N
Ref : Clinical Endocrinology (Oxf) , 41 :129 , 1994
Abstract : A case of congenital goitre with defective thyroglobulin (Tg) synthesis was studied from the clinical, biochemical and morphological perspectives. The patient, 5.5-year-old boy, who was clinically euthyroid, showed a positive perchlorate discharge test (37.2%). However, the iodination system seemed to be normal since radioiodine uptake into the thyroid was very high, and inspection of the H2O2-generating system using thyroid slices and an assay for peroxidase activity in microsomes showed no abnormalities. On the other hand, virtually no Tg was detected in the serum, and the amount of Tg in thyroid tissue, estimated with gel electrophoresis, was below 10% of the normal value, the quality of Tg being unchanged. Morphological observations demonstrated the presence of Tg in the markedly distended rough endoplasmic reticulum of the cytoplasm of follicular cells and a lack of Tg in the colloid of the follicular lumen. These results suggest that the thyroid is defective in Tg synthesis, probably associated with impaired transport of Tg from the cells to the lumen.
ESTHER : Ohyama_1994_Clin.Endocrinol.(Oxf)_41_129
PubMedSearch : Ohyama_1994_Clin.Endocrinol.(Oxf)_41_129
PubMedID: 8050126

Title : Characterization of high-affinity binding sites for diisopropylfluorophosphate (DFP) from chicken spinal cord membranes - Konno_1994_Biochem.Pharmacol_48_2073
Author(s) : Konno N , Suzuki N , Horiguchi H , Fukushima M
Ref : Biochemical Pharmacology , 48 :2073 , 1994
Abstract : The delayed neurotoxic organophosphate [3H]diisopropylfluorophosphate ([3H]DFP) binds with high affinity to membrane-bound proteins from the chicken spinal cord. The DFP binding proteins were solubilized from membrane preparations, using a detergent (CHAPS). The protein(s) sites that labeled with a low concentration of [3H]DFP, e.g. 10(-10)-10(-9) M, were defined as the high-affinity binding sites. The density (or concentration) of the high-affinity binding sites in protein(s) was determined by the difference between total and non-specific binding. The high-affinity binding sites were saturable, and the maximal amount of binding sites was estimated at 400 fmol/mg protein. [3H]DFP binding to solubilized proteins was not completely reversible. Concentration-dependent curves suggested that the [3H]DFP binding sites differ from the active sites of acetylcholinesterase, butyrylcholinesterase, and neuropathy target esterase, as well as from muscarinic acetylcholine receptors. The amount of DFP binding sites after a neurotoxic dose of tri-o-cresyl phosphate (TOCP) decreased markedly in membrane preparations from the chicken spinal cord. These results indicate that a TOCP metabolite(s) interacts with the DFP binding sites in vivo. Gel filtration chromatography of the solubilized membranes indicated at least two major high-affinity DFP binding proteins with apparent molecular weights of 300 and 110 kDa. The DFP binding sites corresponding to the 110 kDa protein were insensitive to eserine, a potent anti-cholinesterase agent.
ESTHER : Konno_1994_Biochem.Pharmacol_48_2073
PubMedSearch : Konno_1994_Biochem.Pharmacol_48_2073
PubMedID: 7802697

Title : Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats - Yoshida_1993_Eur.J.Pharmacol_250_117
Author(s) : Yoshida S , Suzuki N
Ref : European Journal of Pharmacology , 250 :117 , 1993
Abstract : The effects of physostigmine, tacrine and NIK-247 on scopolamine-induced impairment of a passive avoidance response were examined in rats. In addition, we investigated possible peripheral side-effects: miosis and salivation, and central side-effects: hypothermia and tremor which are mediated by cholinergic activation. Intraperitoneal injection of physostigmine reversed scopolamine-induced amnesia at a dose of 0.03 mg/kg. Antiamnesic effects of oral administration of tacrine and NIK-247 were observed at doses of 0.3 and 0.1-0.3 mg/kg, respectively. Intraperitoneal injection of physostigmine induced miosis, salivation, hypothermia and tremor at doses > or = 0.1, 0.3, 0.3 and 1 mg/kg, respectively. Oral administration of tacrine (at doses > or = 0.3 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced miosis. Tacrine (at doses > or = 1 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced hypersalivation. Hypothermia and tremor were observed after administration of tacrine (at doses > or = 10 mg/kg) and NIK-247 (30 mg/kg). The antiamnesic dose of physostigmine was 1/30-1/3 of doses with central or peripheral side-effects. The dose ratio of tacrine was 1/30-1; that of NIK-247 was 1/300-1/10. These results indicate that NIK-247 has higher safety and greater selectivity for cognitive functions than physostigmine or tacrine.
ESTHER : Yoshida_1993_Eur.J.Pharmacol_250_117
PubMedSearch : Yoshida_1993_Eur.J.Pharmacol_250_117
PubMedID: 8119309

Title : Dissociated neurons from normal and mutant Drosophila larval central nervous system in cell culture - Wu_1983_J.Neurosci_3_1888
Author(s) : Wu CF , Suzuki N , Poo MM
Ref : Journal of Neuroscience , 3 :1888 , 1983
Abstract : A primary dissociated cell culture of Drosophila larval central nervous system is reported. Divisions of neuroblasts and vigorous outgrowth of neurites could be observed in culture. Within 24 hr cultured cells exhibited characteristic neuronal morphology and unimpaired ability to synthesize and accumulate acetylcholine. This cell culture system renders easy access to experimental analysis of normal neuronal properties and the altered mechanisms in neurological mutants. Single-channel currents induced by acetylcholine and regenerative action potentials were studied in the somata of the dissociated neurons. The appearance of Na channels in these cultured neurons was demonstrated by the cell lethality induced by veratridine and inhibition of the effect by tetrodotoxin. Dissociated neurons from a temperature-sensitive paralytic mutant napts, in which nerve conduction fails at high temperature, were studied in culture. Neuronal growth was not affected by this mutation, nor by tetrodotoxin. However, napts neurons showed greatly reduced sensitivity to veratridine even at 21 degrees C, a temperature at which napts individuals behave normally. This finding indicates expression of the napts phenotype at a level of isolated single cells and provides independent evidence that napts affects Na channel function.
ESTHER : Wu_1983_J.Neurosci_3_1888
PubMedSearch : Wu_1983_J.Neurosci_3_1888
PubMedID: 6310066