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1.
《BBA》2006,1757(9-10):1133-1143
In cytochrome c oxidase, oxido-reductions of heme a/CuA and heme a3/CuB are cooperatively linked to proton transfer at acid/base groups in the enzyme. H+/e− cooperative linkage at Fea3/CuB is envisaged to be involved in proton pump mechanisms confined to the binuclear center. Models have also been proposed which involve a role in proton pumping of cooperative H+/e− linkage at heme a (and CuA). Observations will be presented on: (i) proton consumption in the reduction of molecular oxygen to H2O in soluble bovine heart cytochrome c oxidase; (ii) proton release/uptake associated with anaerobic oxidation/reduction of heme a/CuA and heme a3/CuB in the soluble oxidase; (iii) H+ release in the external phase (i.e. H+ pumping) associated with the oxidative (R → O transition), reductive (O → R transition) and a full catalytic cycle (R → O → R transition) of membrane-reconstituted cytochrome c oxidase. A model is presented in which cooperative H+/e− linkage at heme a/CuA and heme a3/CuB with acid/base clusters, C1 and C2 respectively, and protonmotive steps of the reduction of O2 to water are involved in proton pumping. 相似文献
2.
《Endocrine practice》2012,18(3):371-375
ObjectiveTo evaluate treatment patterns associated with diabetes medication regimen changes after hospitalization on the basis on preadmission hemoglobin A1c levels.MethodsIn this retrospective database analysis, patients with a diabetes diagnosis, hospitalization, and documented hemoglobin A1c level within the 90 days leading up to hospital admission were identified in an administrative claims database. Treatment regimens were assessed before and after hospitalization. The proportion of patients who had progression, reduction, or no change in therapy was compared across hemoglobin A1c subgroups: hemoglobin A1c < 7.0%, hemoglobin A1c 7.0%-7.9%, and hemoglobin A1c ≥ 8.0%.ResultsFour hundred patients were included (192 in hemoglobin A1c < 7.0% group, 94 in hemoglobin A1c 7.0% 7.9% group, and 114 in hemoglobin A1c ≥ 8.0% group). Demographically, hemoglobin A1c subgroups did not differ significantly (mean age, 57 years; 47.5% male). With respect to therapeutic regimen overall, 28%, 24%, and 48% of patients experienced progression, reduction, and no change, respectively. Across hemoglobin A1c subgroups, 37.7% of patients in the hemoglobin A1c ≥ 8.0% subgroup had therapy progression compared with 26% and 20.2% in the hemoglobin A1c < 7.0% and hemoglobin A1c 7.0%-7.9% subgroups, respectively (P = .032 and P = .006, respectively). Within the progression category, progression via insulin initiation was significantly higher in the hemoglobin A1c ≥ 8.0% subgroup (55.8%) than in the hemoglobin A1c < 7.0% subgroup (16%, P < .001), but not significantly higher than in the hemoglobin A1c 7.0%-7.9% subgroup (36.8%, P = .084). In the hemoglobin A1c ≥ 8.0% subgroup, a lower percentage of patients, 35.1%, experienced no therapy change than in both the hemoglobin A1c < 7.0% subgroup (52.6%) and the hemoglobin A1c 7.0%-7.9% subgroup (54.3%) (P = .003 and P = .006, respectively). There was no difference between subgroups in reduction of therapy.ConclusionsA higher proportion of patients with a hemoglobin A1c level ≥ 8.0% had progression of their antidiabetes therapy after hospitalization and fewer patients had no change in therapy than those in lower hemoglobin A1c subgroups. These data suggest that clinicians may be using hemoglobin A1c measurements to guide discharge planning treatment decisions. (Endocr Pract. 2012;18:371-375) 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(2):644-648
The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α2-adrenergic, and I2 imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ETA receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α2-adrenoceptor antagonist), idazoxan (α2-adrenoceptor/I2-imidazoline antagonist), BU224 (I2-imidazoline antagonist) or BQ123 (endothelin ETA receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED50 values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α2-adrenergic, I2-imidazoline and endothelin ETA receptors are not involved in 1c antinociception. 相似文献
4.
Manisha Khatri Santosh Kumar Rai Sameena Alam Anjana Vij Manisha Tiwari 《Bioorganic & medicinal chemistry》2009,17(5):1890-1897
In an attempt to design novel 5-HT1A agonists/partial agonists, based on an arylpiperazine nucleus, a series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives were synthesized and biologically tested. The anxiolytic effect of the compounds was investigated employing the Elevated plus Maze (EPM) task. On the basis of in vivo functional test, compound 1c (3 mg/kg) and 4c (3 mg/kg) induced significant increments in open arm entries and time on EPM as compared to Buspirone. The anxiolytic effects of compounds 1c and 4c were effectively antagonized by WAY-100635, a 5-HT1A receptor antagonist (0.5 mg/kg). Furthermore, we have also evaluated the concentration of 5-HT in the brain tissue using HPLC with fluorescent detection. Our result showed that serotonin levels were significantly decreased by ~38% (p < 0.001) and ~32% (p < 0.001) after acute administration of compounds 1c and 4c, respectively. These findings suggest that the anxiolytic like activity of these new arylpiperazines is mediated via 5-HT1A receptors in the brain. 相似文献
5.
《Bioorganic & medicinal chemistry》2014,22(15):4257-4268
Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A3AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-d-apio-d-furano- and α-d-apio-l-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N6 of β-d-apio-d-furanoadenosine afforded an A3AR antagonist (10c, Ki = 0.98 μM), while a similar modification of an α-d-apio-l-furanoadenosine gave rise to a partial agonist (11c, Ki = 3.07 μM). The structural basis for this difference was examined by docking to an A3AR model; the antagonist lacked a crucial interaction with Thr94. 相似文献
6.
Angus D. Macaulay Christine K. Hamilton W. Allan King Pawel M. Bartlewski 《Reproductive biology》2013,13(1):41-50
This study was designed to determine if the addition of androgens at ovarian follicular fluid (FF) concentrations to oocyte maturation media would alter the development and sex ratio of bovine embryos. To maximize hormone bioavailability, oil was removed and glass culture dishes were used during in vitro maturation (IVM) phase; this modified system was then used in the present experiment along with the standard IVM system utilizing plastic containers and incubation under oil. Ethanol (0.2%) was the vector for steroid hormone delivery. Oocytes were incubated for 22 h in the presence of two doses (“low” and “high”) of androstenedione (A4) or testosterone (T); the doses were based on the concentrations of both androgens in preovulatory bovine follicles (A4: 337.5 and 562.5 ng/ml; T: 22.2 and 42.6 ng/ml). The results of hormone assays indicated that bioavailability of steroid hormones remained relatively constant, regardless of the IVM system used. The plasticware with the addition of T resulted in significantly higher cleavage rates (80.0 ± 2.1%) than any other combination of treatments (plasticware × A4: 71.5 ± 2.6%; glassware × T: 71.2 ± 1.9%; and glassware × A4: 71.4 ± 2.4%). The blastocyst formation rate for the plasticware × T treatment (39.7 ± 2.5%) was significantly greater than for all other combinations (glassware × T: 28.7 ± 2.2%; glassware × A4: 24.0 ± 2.8%; and plasticware × A4: 19.8 ± 3.0%) and the low dose of T (37.1 ± 2.5%) resulted in higher (p < 0.05) blastocyst formation rates than all other treatments (T high dose: 29.2 ± 2.5%; A4 high dose: 27.1 ± 2.9%; and A4 low dose: 20.2 ± 3.0%). The proportion of male embryos was greater (p < 0.05) in plastic than glass dishes in the low-dose A4 group (59.1 ± 8.7% vs. 38.2 ± 5.5%, plasticware vs. glassware, respectively) and it tended to be greater (p < 0.08) in the control groups and high-dose A4 group, but not in the T groups. There was a moderate positive correlation between blastocyst formation rates across all treatment and control groups, and the percentage of male bovine embryos (r = 0.38, p < 0.05). In summary, specific combinations of androgen and glassware/plasticware treatments did alter early bovine embryo development and sex ratio. The addition of T to IVM media increased the cleavage and blastocyst formation rates in plasticware and may be employed to improve the efficiency of the standard in vitro embryo production systems. Androstenedione appeared to enhance whereas testosterone nullified the deviation in sex ratio (pro-femaleness) associated with the use of glass IVM dishes. 相似文献
7.
Bin Liu Yang Zhang J. Timothy Sage S. Michael Soltis Tzanko Doukov Ying Chen C. David Stout James A. Fee 《BBA》2012,1817(4):658-665
The purpose of the work was to provide a crystallographic demonstration of the venerable idea that CO photolyzed from ferrous heme-a3 moves to the nearby cuprous ion in the cytochrome c oxidases. Crystal structures of CO-bound cytochrome ba3-oxidase from Thermus thermophilus, determined at ~ 2.8–3.2 Å resolution, reveal a Fe–C distance of ~ 2.0 Å, a Cu–O distance of 2.4 Å and a Fe–C–O angle of ~ 126°. Upon photodissociation at 100 K, X-ray structures indicate loss of Fea3–CO and appearance of CuB–CO having a Cu–C distance of ~ 1.9 Å and an O–Fe distance of ~ 2.3 Å. Absolute FTIR spectra recorded from single crystals of reduced ba3–CO that had not been exposed to X-ray radiation, showed several peaks around 1975 cm? 1; after photolysis at 100 K, the absolute FTIR spectra also showed a significant peak at 2050 cm? 1. Analysis of the ‘light’ minus ‘dark’ difference spectra showed four very sharp CO stretching bands at 1970 cm? 1, 1977 cm? 1, 1981 cm? 1, and 1985 cm? 1, previously assigned to the Fea3–CO complex, and a significantly broader CO stretching band centered at ~ 2050 cm? 1, previously assigned to the CO stretching frequency of CuB bound CO. As expected for light propagating along the tetragonal axis of the P43212 space group, the single crystal spectra exhibit negligible dichroism. Absolute FTIR spectrometry of a CO-laden ba3 crystal, exposed to an amount of X-ray radiation required to obtain structural data sets before FTIR characterization, showed a significant signal due to photogenerated CO2 at 2337 cm? 1 and one from traces of CO at 2133 cm? 1; while bands associated with CO bound to either Fea3 or to CuB in “light” minus “dark” FTIR difference spectra shifted and broadened in response to X-ray exposure. In spite of considerable radiation damage to the crystals, both X-ray analysis at 2.8 and 3.2 Å and FTIR spectra support the long-held position that photolysis of Fea3–CO in cytochrome c oxidases leads to significant trapping of the CO on the CuB atom; Fea3 and CuB ligation, at the resolutions reported here, are otherwise unaltered. This article is part of a Special Issue entitled: Respiratory Oxidases. 相似文献
8.
A combined DFT/electrostatic approach is employed to study the coupling of proton and electron transfer reactions in cytochrome c oxidase (CcO) and its proton pumping mechanism. The coupling of the chemical proton to the internal electron transfer within the binuclear center is examined for the O → E transition. The novel features of the His291 pumping model are proposed, which involve timely well-synchronized sequence of the proton-coupled electron transfer reactions. The obtained pKas and Ems of the key ionizable and redox-active groups at the different stages of the O → E transition are consistent with available experimental data. The PT step from E242 to H291 is examined in detail for various redox states of the hemes and various conformations of E242 side-chain. Redox potential calculations of the successive steps in the reaction cycle during the O → E transition are able to explain a cascade of equilibria between the different intermediate states and electron redistribution between the metal centers during the course of the catalytic activity. All four electrometric phases are discussed in the light of the obtained results, providing a robust support for the His291 model of proton pumping in CcO. This article is part of a Special Issue entitled: Respiratory oxidases. 相似文献
9.
Derong Ding Justin R. Nickell Agripina G. Deaciuc Narsimha Reddy Penthala Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry》2013,21(21):6771-6777
Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a–15c and 22a–22c) potently inhibited [3H]dopamine (DA) uptake into isolated synaptic vesicles (Ki ? 66 nM). The cis-4-methoxy analog 22b was the most potent inhibitor (Ki = 24 nM), and was twofold more potent that either lobelane (2a, Ki = 45 nM) or norlobelane (2b, Ki = 43 nM). The trans-methylenedioxy analog, 15c (Ki = 31 nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse. 相似文献
10.
《BBA》2006,1757(9-10):1122-1132
The PM → F transition of the catalytic cycle of cytochrome c oxidase from bovine heart was investigated using single-electron photoreduction and monitoring the subsequent events using spectroscopic and electometric techniques. The PM state of the oxidase was generated by exposing the oxidized enzyme to CO plus O2. Photoreduction results in rapid electron transfer from heme a to oxoferryl heme a3 with a time constant of about 0.3 ms, as indicated by transients at 605 nm and 580 nm. This rate is ∼ 5-fold more rapid than the rate of electron transfer from heme a to heme a3 in the F → O transition, but is significantly slower than formation of the F state from the PR intermediate in the reaction of the fully reduced enzyme with O2 to form state F (70–90 μs). The ∼ 0.3 ms PM → F transition is coincident with a rapid photonic phase of transmembrane voltage generation, but a significant part of the voltage associated with the PM → F transition is generated much later, with a time constant of 1.3 ms. In addition, the PM → F transition of the R. sphaeroides oxidase was also measured and also was shown to have two phases of electrogenic proton transfer, with τ values of 0.18 and 0.85 ms. 相似文献
11.
《Biochimica et Biophysica Acta (BBA)/General Subjects》2014,1840(9):2886-2903
BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of β-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress.MethodsThe following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ1–42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies.ResultsWe synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβ aggregation inhibitory activity. Compound 9g had 74% Aβ1–42 aggregation inhibitory effect at 10 μM concentration with its IC50 value of 6.5 μM for self-induced Aβ1–42 aggregation. This compound also showed good inhibition of metal-mediated (Cu2 + and Fe2 +) and acetylcholinesterase-induced Aβ1–42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC50 values of 0.86 μM and 0.51 μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29.ConclusionsCompound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease.General significanceCompound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment. 相似文献
12.
Cytochrome c oxidase (CcO) catalyzes the reduction of molecular oxygen to water using ferrocytochrome c (cyt c2 +) as the electron donor. In this study, the oxidation of horse cyt c2 + by CcO from Rhodobacter sphaeroides, was monitored using stopped-flow spectrophotometry. A novel analytic procedure was applied in which the spectra were deconvoluted into the reduced and oxidized forms of cyt c by a least-squares fitting method, yielding the reaction rates at various concentrations of cyt c2 + and cyt c3 +. This allowed an analysis of the effects of cyt c3 + on the steady-state kinetics between CcO and cyt c2 +. The results show that cyt c3 + exhibits product inhibition by two mechanisms: competition with cyt c2 + at the catalytic site and, in addition, an interaction at a second site which further modulates the reaction of cyt c2 + at the catalytic site. These results are generally consistent with previous reports, indicating the reliability of the new procedure. We also find that a 6 × His-tag at the C-terminus of the subunit II of CcO affects the binding of cyt c at both sites. The approach presented here should be generally useful in spectrophotometric studies of complex enzyme kinetics. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). 相似文献
13.
《Bioorganic & medicinal chemistry》2016,24(12):2794-2808
A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1–31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22–31) displayed nanomolar affinity for the hA2A AR (Ki = 3.62–57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3–22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki = 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs. 相似文献
14.
Narsimha Reddy Penthala Purushothama Rao Ponugoti Justin R. Nickell Agripina G. Deaciuc Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry letters》2013,23(11):3342-3345
Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a–i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [3H]-DTBZ binding (Ki = 560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki = 8.29 μM). Analog 11f also showed similar potency of inhibition of [3H]-DA uptake into vesicles (Ki = 45 nM) compared to that for GZ-793A (Ki = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function. 相似文献
15.
The 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) is a key enzyme in the aromatic amino acid biosynthetic pathway in microorganisms and plants, which catalyzes the formation of 5-enolpyruvylshikimate-3-phosphate (EPSP) from shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP). In this study, a novel AroA-encoding gene was identified from the deep sea bacterium Alcanivorax sp. L27 through screening the genomic library and termed as AroAA.sp. A phylogenetic analysis revealed that AroAA.sp (1317 bp and 438 amino acids) is a class II AroA. This enzyme exhibited considerable activity between pH 5.5 and pH 8.0 and notable activity at low temperatures. The KM for PEP and IC50 [glyphosate] values (the concentration of glyphosate that inhibited enzyme activity by 50%) of AroAA.sp were 78 μM and 1.5 mM, respectively. Furthermore, site-directed mutagenesis revealed that the G100A mutant had a 30-fold increase in the IC50 [glyphosate] value; while the L105P mutant showed only 20% catalytic activity compared to wild-type AroAA.sp. The specific activity of the wild-type AroAA.sp, the G100A mutant and the L105P mutant were 7.78 U/mg, 7.26 U/mg and 1.76 U/mg, respectively. This is the first report showing that the G100A mutant of AroA displays considerably improved glyphosate resistance and demonstrates that Leu105 is essential for the enzyme's activity. 相似文献
16.
Two series of new thiazolidin-4-one derivatives 4a–c and 8a–e were designed and prepared. All the synthesized compounds were evaluated for their in vitro COX-2 selectivity and anti-inflammatory activity in vivo. Compounds 8c and 8d showed the best overall in vitro COX-2 selectivity (selectivity indexes of 4.56 and 5.68 respectively) and in vivo activities (edema inhibition % = 61.8 and 67 after 3 h, respectively) in comparison with the reference drug celecoxib (S.I. = 7.29, edema inhibition % = 60 after 3 h). In addition, 8c and 8d were evaluated for their mean effective anti-inflammatory doses (ED50 = 27.7 and 18.1 μmol/kg respectively, celecoxib ED50 = 28.2 μmol/kg) and ulcerogenic liability (reduction in ulcerogenic potential versus celecoxib = 85%, 92% respectively. Molecular docking studies were performed and the results were in agreement with that obtained from the in vitro COX inhibition assays. 相似文献
17.
《Bioorganic & medicinal chemistry》2016,24(21):5462-5480
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5 nM, A2A: 230 nM; Ki rat A1: 352 nM, A2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642 nM, A2A: 203 nM; Ki rat A1: 166 nM, A2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393 nM, human A2A: 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. 相似文献
18.
Jitesh R. Shah Philip D. Mosier Srinivas Peddi Bryan L. Roth Richard B. Westkaemper 《Bioorganic & medicinal chemistry letters》2010,20(3):935-938
Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT2A and H1 receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75–25% ratio was found to have an apparent Ki of 10 nM at the 5-HT2A receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT2A receptor (Ki = 21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT2A over the H1 receptor (Ki = 2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT2A and H1 receptors (Ki = 223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT2A binding site. 相似文献
19.
Babasaheb P. Bandgar Shrikant S. Gawande Suchita C. Warangkar Jalinder V. Totre 《Bioorganic & medicinal chemistry》2010,18(10):3618-3624
An efficient solvent-free procedure for the synthesis of thiomorpholides in the presence of a catalytic amount of solid-supported fluoroboric acid (HBF4–SiO2) is described. The advantages of this method are high yields, short reaction times, ease of product isolation, low cost, and the catalyst can be recycled for a number of times without significant loss of activity. Three thiomorpholides possessing electron-donating group (4c, 4g, and 4h) were exhibiting excellent stimulatory activities against Erwinia carotovora l-asparaginase. The most potent activator, compound 4h displayed the following kinetic parameters, Km = 75 μM and Vmax = 1000 μmol mg?1 min?1 and KA = 0.985 μM. Furthermore, these compounds (4g, 4h, 4c, 4f, 4a, and 4d) have also shown promising 2,2′-diphenyl-1-picrylhydrazyl (DPPH) reducing antioxidant activity (21–36%) at 1 mM concentration as compared to standard butylated hydroxyl anisole (72% at 1 mM). 相似文献
20.
《Endocrine practice》2011,17(1):41-50
ObjectiveTo compare efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) with insulin (glargine) in type 2 diabetic patients who were not maintaining glycemic control on basal insulin and oral antidiabetic drugs.MethodsIn a 24-week, open-label, parallel-group trial, type 2 diabetic patients who were not maintaining glycemic control on basal insulin (glargine or neutral protamine Hagedorn) + oral antidiabetic drugs were randomly assigned to twice-daily BIAsp 30 + metformin or oncedaily glargine + metformin + secretagogues (secretagogues were discontinued in the BIAsp 30 arm).ResultsOne hundred thirty-seven patients were randomly assigned to the BIAsp 30 group and 143 patients were randomly assigned to the glargine group. Of 280 patients randomized, 229 (81.8%) completed the study. End-of-trial hemoglobin A1c reductions were − 1.3% (BIAsp 30) vs − 1.2% (glargine) (treatment difference: 95% confidence interval, − 0.06 [− 0.32 to 0.20]; P = .657). Of patients taking BIAsp 30, 27.3% reached a hemoglobin A1c level < 7.0% compared with 22.0% of patients taking glargine (treatment difference: P = .388). Glucose increment averaged over 3 meals was lower in the BIAsp 30 arm (treatment difference: − 17.8 mg/dL, P = .001). Fasting plasma glucose reductions from baseline were − 13.8 mg/ dL (BIAsp 30) vs − 42.5 mg/dL (glargine) (P = .0002). Final minor hypoglycemia rate, insulin dose, and weight change were higher in the BIAsp 30 arm (6.5 vs 3.4 events/patient per year, P <.05; 1.19 vs 0.63 U/kg; and 3.1 vs 1.4 kg, P = .0004, respectively).ConclusionsDespite not receiving secretagogues, patients taking BIAsp 30 + metformin achieved similar hemoglobin A1c levels and lower postprandial plasma glucose compared with those receiving glargine + metformin + secretagogues. The large improvement in the glargine group suggests the patients were not true basal failures at randomization. While switching to BIAsp 30 improves glycemic control in this patient population, remaining on basal insulin and optimizing the dose may be equally effective in the short term. (Endocr Pract. 2011;17:41-50) 相似文献