共查询到20条相似文献,搜索用时 15 毫秒
1.
Takács B Csoknya M Gábriel R Nagy G 《Journal of biochemical and biophysical methods》2007,70(5):713-720
Distribution of serotonin (5-HT) content of nervous fibers in both the somatic and the visceral muscle of Eisenia fetida have been investigated using immunocytochemical staining and voltammetric measurements. The somatic muscles in the body wall are richer innervated with serotoninergic fibers than the visceral ones in the pharynx and gizzard. The relative density of immunopositive fibers in the circular muscle layer of the body wall was found to be 2.73% while in the prostomium it was 1.02%. In the case of the muscle in pharynx 1.12% and in gizzard 1.28% density values were found. Differential Pulse Voltammetric (DPV) measurements with carbon fiber electrodes in the above mentioned muscle layers gave 272.5 nA, 135.0 nA, 122.5 nA, 137.5 nA peak heights, respectively. In the statistical analysis T-test was used at a confidence level of 95% (p<0.05). DPV current peak (i(p)) values reflect clearly the 5-HT concentration differences. Significant correlation was found between the innervation density and the i(p) values recorded in different areas. The i(p) values recorded at different times in different locations are determined by instantaneous serotonin concentration of the living tissue. As far as we know this is the first report using in vivo voltammetry investigating serotonin content in earthworm, E. fetida. 相似文献
2.
《Bioorganic & medicinal chemistry》2016,24(8):1619-1636
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi = 8.4, DA D2 pKi = 6.0 and hERG fpKi = 5.2) showed a balanced profile and further refinements are in progress around this molecule. 相似文献
3.
Marhaba Hojahmat David B. Horton Seth D. Norrholm Dennis K. Miller Vladimir P. Grinevich Agripina Gabriela Deaciuc Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry》2010,18(2):640-649
Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at α4β21 nicotinic acetylcholine receptors, has moderate affinity (Ki = 5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2–20 of lobeline were synthesized and evaluated for interaction with α4β21 and α71 neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α71 nAChRs. Similar to lobeline (Ki = 4 nM), sulfonic acid esters had high affinity at α4β21 (Ki = 5–17 nM). Aromatic carboxylic acid ester analogs of lobeline (2–4) were 100–1000-fold less potent than lobeline at α4β21 nAChRs, whereas aliphatic carboxylic acid ester analogs were 10–100-fold less potent than lobeline at α4β21. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the 36Rb+ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC50 values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13–45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (Ki = 1.98–10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β21 nAChRs (Ki = 19.3 μM) and was equipotent with lobeline, at VMAT2 (Ki = 2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2. 相似文献
4.
Amber Thaxton Sari Izenwasser Dean Wade Edwin D. Stevens David L. Mobley Vivian Jaber Stacey A. Lomenzo Mark L. Trudell 《Bioorganic & medicinal chemistry letters》2013,23(15):4404-4407
A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki = 1.0 nM) and the tetrachloro substituted derivative 7i (Ki = 1.3 nM) possessing low nanomolar affinity for the SERT. The 3-(3,4-dichlorophenyl-3-phenylmethoxyazetidine (7g) exhibited moderate affinity at both DAT and SERT transporters and suggests that substitution of the aryl rings can be used to tune the mononamine transporter affinity. 相似文献
5.
Gergely Varga Tibor Docsa Pál Gergely László Juhász László Somsák 《Bioorganic & medicinal chemistry letters》2013,23(6):1789-1792
Di-O-cinnamoylated, -p-coumaroylated, and -feruloylated d-, l- and meso-tartaric acids were synthesized as analogues of the natural product FR258900, a glycogen phosphorylase (GP) inhibitor with in vivo antihyperglycaemic activity. The new compounds inhibited rabbit muscle GP in the low micromolar range, and bound to the allosteric site of the enzyme. The best inhibitor was 2,3-di-O-feruloyl meso-tartaric acid and had Ki values of 2.0 μM against AMP (competitive) and 3.36 μM against glucose-1-phosphate (non-competitive). 相似文献
6.
Do Young Kim Mi Kyoung Han Hyun-Woo Oh Doo-Sang Park Su-Jin Kim Seung-Goo Lee Dong-Ha Shin Kwang-Hee Son Kyung Sook Bae Ho-Yong Park 《Journal of Molecular Catalysis .B, Enzymatic》2010,62(1):32-39
A novel GH10 endo-β-1,4-xylanase (XylG) gene from Streptomyces thermocarboxydus HY-15, which was isolated from the gut of Eisenia fetida, was cloned, over-expressed, and characterized. The XylG gene (1182 bp) encoded a polypeptide of 393 amino acids with a deduced molecular mass of 43,962 Da and a calculated pI of 6.74. The primary structure of XylG was 69% similar to that of Thermobifida fusca YX endo-β-1,4-xylanase. It was most active at pH 6.0 and 55 °C. The susceptibilities of xylans to XylG were as follows: oat spelt xylan > birchwood xylan > beechwood xylan. The XylG also showed high activity (474 IU/mg) toward p-nitrophenylcellobioside. Moreover, at pH 6.0 and 50 °C, the Vmax and Km values of the XylG were 127 IU/mg and 2.51 mg/ml, respectively, for oat spelt xylan and 782 IU/mg and 5.26 mM, respectively, for p-nitrophenylcellobioside. A homology model indicated that XylG folded to form a (β/α)8-barrel with two catalytic residues of an acid/base (Glu181) and a nucleophile (Glu289). The formation of a disulfide bond between Cys321 and Cys327 were predicted by homology modeling. 相似文献
7.
8.
Andreas Nievergelt Peter Huonker Roland Schoop Karl-Heinz Altmann Jürg Gertsch 《Bioorganic & medicinal chemistry》2010,18(9):3345-3351
Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT1A receptor with significant to moderate binding affinities (Ki = 3–20 μΜ). [35S]-GTPγS assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (Ki = 11.6 μg/ml) partially activate the 5-HT1A receptor (20–60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT1A active compounds. 相似文献
9.
J. Greig Inglis Rene Vandenboom David A. Gabriel 《Journal of electromyography and kinesiology》2013,23(6):1289-1294
Sex-differences in the maximum rate of torque development (dτ/dtmax) may be due to differences in maximum muscle strength, because higher torque values mathematically lead to higher values for the rate of change in torque. The rate of change in the isometric torque-time curve is often normalized to the isometric maximum voluntary contraction (MVC) to evaluate males and females on a relative scale. Normalization eliminates sex-differences in dτ/dtmax in the lower limbs because males and females are more comparable (i.e., differences between the sexes are relatively small) with respect to both muscle size and strength. However, normalization fails to result in parody in dτ/dtmax of the upper limb, leading to the idea that other factors may be involved. This study determined if sex-differences in dτ/dtmax in the upper limb can be attributed to differences in isometric MVC and/or a neural variable related to rate of increase in muscle activation (Q30). Forty-six participants (23 males, 23 females) performed maximal isometric elbow flexion contractions, “as hard and as fast as possible”. Maximum torque (τmax), dτ/dtmax, and the rate of increase in surface electromyographic (sEMG) activity (Q30) were assessed. Muscle plus bone cross-sectional area (M + B CSA) of the upper arm was calculated to estimate differences in muscle size, only for comparative purposes. Maximum strength (55.5%) and muscle size (41.9%) of the elbow flexors in males were much greater than that of females (p < 0.05). There was a large difference (61.2%) between males and females with respect to dτ/dtmax that was reduced by statistical correction using an analysis of covariance (ANCOVA). The percent differences were reduced to 36.7% (p < 0.05) for τmax and 54.4% (p < 0.05) for Q30, but was nearly eliminated to 13.8% (p > 0.05) when both variables were used simultaneously as covariates. Since sex-differences in the upper limb dτ/dtmax persist, additional neural or biomechanical factors may be involved. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2014,24(10):2236-2239
Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R) = 9.3) c log S, c log P, LE, LipE, and LELP values of −2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH3R) = 8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively. 相似文献
11.
Ermitas Alcalde Neus Mesquida Sara López-Pérez Jordi Frigola Ramon Mercè Jörg Holenz Marta Pujol Enrique Hernández 《Bioorganic & medicinal chemistry》2009,17(20):7387-7397
Further studies in quest of 5-HT6 serotonin receptor ligands led to the design and synthesis of a few selected examples of N-(inden-5-yl)sulfonamides with a ring-constrained aminoethyl side chain at the indene 3-position, some of which exhibited a high binding affinity, such as the pyrrolidine analogue 28 (Ki = 3 nM). Moreover, the structurally abbreviated N-(inden-5-yl)sulfonamides showed Ki values ?43 nM, which indicates that neither the N,N-aminoethyl nor the conformationally restricted aminoethyl side arm at the indene 3-position are required for binding. Selected compounds were then tested in a functional cAMP stimulation assay and found to act as 5-HT6 antagonists, although with moderate potency at the micromolar level. 相似文献
12.
Haifeng Sun Liyuan Zhu Huicui Yang Wangke Qian Lin Guo Shengbin Zhou Bo Gao Zeng Li Yu Zhou Hualiang Jiang Kaixian Chen Xuechu Zhen Hong Liu 《Bioorganic & medicinal chemistry》2013,21(4):856-868
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia. 相似文献
13.
Yoon Jin Kwon Simon Saubern James M. Macdonald Xi-Ping Huang Vincent Setola Bryan L. Roth 《Bioorganic & medicinal chemistry letters》2010,20(18):5488-5490
The serendipitous discovery of N-cyclohexyl-8-fluoro-3,3a,4,9b-tetrahydro-1H-thiochromeno[4,3-c]isoxazole-1-carboxamide as a selective human serotonin 5-HT2B antagonist with Ki of 42 ± 5 nM is reported herein. A subsequent functional assay indicated little agonist activity compared to 5-HT itself. 相似文献
14.
Inhibition of wheat β-amylase (WBA) by glucose and maltose was studied by kinetics and thermodynamics. The inhibitory effects of fructose, difructose, sucrose, trehalose, cellobiose, acarbose, and 1-deoxynojirimycin on WBA were also evaluated. The half maximal inhibitory concentrations (IC50) of acarbose, maltose and glucose were 0.06 ± 0.01 M, 0.22 ± 0.09 M, and 1.41 ± 0.17 M, respectively. The inhibitor constant (Ki) and the thermodynamic parameters such as changes in Gibbs energy (ΔG), enthalpy (ΔH), and entropy (ΔS) of the dissociation reactions of the WBA-glucose and WBA-maltose complexes were temperature and pH-dependent. The dissociation reactions were endothermic and enthalpy-driven. Both glucose and maltose behaved as competitive inhibitors at pH 3.0 and 5.4 at a temperature of 25 °C with respective Ki values of 0.33 ± 0.02 M and 0.12 ± 0.03 M. In contrast, both sugars exhibited uncompetitive inhibition at pH 9 at a temperature of 25 °C with Ki values of 0.21 ± 0.03 M for glucose and 0.11 ± 0.04 M for maltose. The pH-dependence of the inhibition type and Ki values indicate that the ionizing groups of WBA influence drastically the interaction with these carbohydrates. This evidence enables us to consider temperature and pH in the WBA-catalyzed hydrolysis to manipulate the inhibition by end-product, maltose, and even by glucose. 相似文献
15.
Morten Jørgensen Pernille N. Jørgensen Claus T. Christoffersen Klaus G. Jensen Thomas Balle Benny Bang-Andersen 《Bioorganic & medicinal chemistry》2013,21(1):196-204
The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α1A-adrenoceptor ligands with Ki values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D2 receptors. Compound 3i showed almost equal affinity for α1B- (Ki = 1.9 nM) and α1D-adrenoceptors (Ki = 2.5 nM) as for α1A, as well as moderate affinity for 5-HT1B (Ki = 13 nM) and 5-HT6 (Ki = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands. 相似文献
16.
Roland Müller Kurt Strässle Brigitte Wirth 《Journal of electromyography and kinesiology》2010,20(5):845-850
The validity of the Sorensen test as a measure for back muscle endurance is controversial due to a possible impact of hip extensor muscles. The aim of this study was to investigate the criterion validity of an alternative test (Ito test) compared to the Sorensen test. Both procedures were performed by 29 healthy subjects (11 women) for 5 s and until exhaustion (randomized order). EMG activity was measured from 3 lumbar back and 3 hip extensor muscles. Muscular involvement in test positions was calculated as percentage of maximal voluntary contraction (MVC). Muscle fatigue was determined by the normalized regression coefficient of the median frequencies of the EMG power spectrum (NMFslope). Prediction of holding time by NMFslope values was investigated using regression analysis. In the test positions, the hamstring muscles were activated to a higher MVC percentage in the Sorensen than in the Ito test, while the iliocostalis muscle was less activated. Similarly, the iliocostalis (p = 0.006) and the multifidi muscles (p = 0.03) significantly contributed to predict holding time in the Ito test, whereas the multifidi muscles (p = 0.001) and the semitendinosus muscle (p = 0.046) did so in the Sorensen test. The results of this study indicate that the Ito test might present a valuable alternative for testing back muscle endurance in LBP patients. 相似文献
17.
We aimed to characterize rectus abdominis, internal oblique, and external oblique muscle activity in healthy adults under expiratory resistance using surface electromyography. We randomly assigned 42 healthy adult subjects to 3 groups: 30%, 20%, and 10% maximal expiratory intraoral pressure (PEmax). After measuring 100% PEmax and muscle activity during 100% PEmax, the activity and maximum voluntary contraction of each muscle during the assigned experimental condition were measured. At 100% PEmax, the external oblique (p < 0.01) and internal oblique (p < 0.01) showed significantly elevated activity compared with the rectus abdominis muscle. Furthermore, at 20% and 30% PEmax, the external oblique (p < 0.05 and < 0.01, respectively) and the internal oblique (p < 0.05 and < 0.01, respectively) showed significantly elevated activity compared with the rectus abdominis muscle. At 10% PEmax, no significant differences were observed in muscle activity.Although we observed no significant difference between 10% and 20% PEmax, activity during 30% PEmax was significantly greater than during 20% PEmax (external oblique: p < 0.05; internal oblique: p < 0.01). The abdominal oblique muscles are the most active during forced expiration. Moreover, 30% PEmax is the minimum intensity required to achieve significant, albeit very slight, muscle activity during expiratory resistance. 相似文献
18.
Jyothi Matharu Jun Oki David R. Worthen Quentin R. Smith Peter A. Crooks 《Bioorganic & medicinal chemistry letters》2010,20(12):3688-3691
Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood–brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had Ki values in the range 2.1–8.5 μM with greater affinities than that of either l-phenylalanine (Ki = 11 μM) or melphalan (Ki = 55 μM), but lower than dl-2-NAM-7 (Ki = 0.08 μM). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the dl-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity. 相似文献
19.
Razieh Eskandari Kyra Jones David R. Rose B. Mario Pinto 《Bioorganic & medicinal chemistry letters》2010,20(19):5686-5689
Ponkoranol is a naturally occurring glucosidase inhibitor isolated from the plant Salacia reticulata. The compound comprises a sulfonium ion with an internal sulfate counter ion. We report here an efficient synthetic route to 3′-O-methyl ponkoranol to test the hypothesis that occupation of a hydrophobic pocket by a methyl group instead of the polar sulfate ion within the active site of human N-terminal maltase glucoamylase would be beneficial. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-d-arabinitol at the C-6 position of benzyl 6-O-p-toluenesulfonyl β-d-glucopyranoside, followed by deprotection using boron trichloride and reduction with sodium borohydride. The target compound inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase (ntMGAM) with a Ki value of 0.50 ± 0.04 μM, higher than those of de-O-sulfonated ponkoranol (Ki = 43 ± 3 nM), or its 5′-stereoisomer (Ki = 15 ± 1 nM). We conclude that the interaction of the methyl group with hydrophobic residues in the active site is not as beneficial to inhibition of ntMGAM as the other interactions of the polyhydroxylated chain with active-site residues. 相似文献
20.
François Hug Paul W. Hodges Kylie J. Tucker 《Journal of electromyography and kinesiology》2013,23(6):1413-1420
IntroductionWe aimed to determine whether the changes in muscle activity (in terms of both gross electromyography (EMG) and motor unit (MU) discharge characteristics) observed during pain are spatially organized with respect to pain location within a muscle which is the main contributor of the task.MethodsSurface and fine-wire EMG was recorded during matched low-force isometric plantarflexion from soleus (from four quadrants with fine-wire EMG and from the medial/lateral sides with surface EMG), both gastrocnemii heads, peroneus longus, and tibialis anterior. Four conditions were tested: two control conditions that each preceded contractions with pain induced in either the lateral (PainL) or medial (PainM) side of soleus.ResultsNeither the presence (p = 0.28) nor location (p = 0.19) of pain significantly altered gross muscle activity of any location (lateral/medial side of soleus, gastrocnemii, peroneus longus and tibialis anterior). Group data from 196 MUs show redistribution of MU activity throughout the four quadrants of soleus, irrespective of pain location. The significant decrease of MU discharge rate during pain (p < 0.0001; PainL: 7.3 ± 0.9–6.9 ± 1.1 Hz, PainM: 7.0 ± 1.1 to 6.6 ± 1.1 Hz) was similar for all quadrants of the soleus (p = 0.43), regardless of the pain location (p = 0.98). There was large inter-participant variation in respect to the characteristics of the altered MU discharge with pain.ConclusionResults from both surface and fine-wire EMG recordings do not support the hypothesis that muscle activity is reorganized in a simple systematic manner with respect to pain location. 相似文献