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41.
O. V. Tikhonova A. V. Veselovsky A. E. Medvedev A. S. Ivanov 《Molecular simulation》2013,39(4-6):379-389
Abstract The monoamine oxidase catalyses the oxidative deamination of neuroactive amines. This enzyme exists in two forms A and B, which differ by substrates preference and inhibitors specificity. Investigation of the structures of these enzymes and design new selective inhibitors are of greatly interesting since MAO A inhibitors are used in therapeutic practice as antidepressants and MAO B inhibitors – in the treatment Parkinson's diseases. The three dimension structures of monoamine oxidases are still unknown. Therefore, one of the most perspective approach to define significant features of structure active site is method based on analysis of structure-activity relationship (3D QSAR) with comparison of molecular fields analysis (CoMFA) allowing to get the spatial distribution of important properties affecting the activity. In present study we investigate the structures of active sites MAO A and B using 16 pyrazinocarbazole derivatives in variant conformation. Majority of pyrazinocarbazole derivatives have a rigit conformation, but three of those is sufficiently flexible. The latters can be in two conformation types: long molecules (substitution accommodate along axis of main structure) and short molecules (substitution accommodate at acute angle about of main structure). Several 3D QSAR and CoMFA models of MAO A and B active sites were design for data sets containing various types of flexible molecules conformation. All obtained models are statistical reliable and have sufficient predictive power for tested compound tetrindole. The best MAO A model that include two flexible molecules in long conformations was obtained, and the longest one of those in short conformation. In contrast, for MAO B model containing all flexible molecules in the short conformations is more preferred. On the basis of obtained data the schematic models of MAO A and B active sites structures are proposed. According to these models MAO A active site have the narrow long cavity that accommodate long molecules, while MAO B active site is broader and shorter. 相似文献
42.
Sonja Sucic Florian Koban Ali El-Kasaby Oliver Kudlacek Thomas Stockner Harald H. Sitte Michael Freissmuth 《The Journal of biological chemistry》2013,288(8):5330-5341
The serotonin transporter (SERT) maintains serotonergic neurotransmission via rapid reuptake of serotonin from the synaptic cleft. SERT relies exclusively on the coat protein complex II component SEC24C for endoplasmic reticulum (ER) export. The closely related transporters for noradrenaline and dopamine depend on SEC24D. Here, we show that discrimination between SEC24C and SEC24D is specified by the residue at position +2 downstream from the ER export motif (607RI608 in SERT). Substituting Lys610 with tyrosine, the corresponding residue found in the noradrenaline and dopamine transporters, switched the SEC24 isoform preference: SERT-K610Y relied solely on SEC24D to reach the cell surface. This analysis was extended to other SLC6 (solute carrier 6) transporter family members: siRNA-dependent depletion of SEC24C, but not of SEC24D, reduced surface levels of the glycine transporter-1a, the betaine/GABA transporter and the GABA transporter-4. Experiments with dominant negative versions of SEC24C and SEC24D recapitulated these findings. We also verified that the presence of two ER export motifs (in concatemers of SERT and GABA transporter-1) supported recruitment of both SEC24C and SEC24D. To the best of our knowledge, this is the first report to document a change in SEC24 specificity by mutation of a single residue in the client protein. Our observations allowed for deducing a rule for SLC6 family members: a hydrophobic residue (Tyr or Val) in the +2 position specifies interaction with SEC24D, and a hydrophilic residue (Lys, Asn, or Gln) recruits SEC24C. Variations in SEC24C are linked to neuropsychiatric disorders. The present findings provide a mechanistic explanation. Variations in SEC24C may translate into distinct surface levels of neurotransmitter transporters. 相似文献
43.
Obulakshmi Arapulisamy Padmanabhan Mannangatti Lankupalle D. Jayanthi 《The Journal of biological chemistry》2013,288(40):28599-28610
Neurokinin-1 receptor (NK1R) mediates down-regulation of human norepinephrine (NE) transporter (hNET) via protein kinase C (PKC). However, native NET regulation by NK1R and the mechanism by which NK1R targets NET among other potential effectors are unknown. Effect of NK1R activation on native NET regulation and NET/NK1R interaction were studied using rat brain synaptosomes expressing native NET and NK1R as well as human placental trophoblast (HTR) cells coexpressing WT-hNET or NK1R/PKC-resistant hNET-T258A,S259A double mutant (NET-DM) and hNK1R. The selective NK1R agonist, GR73632, and Substance-P (SP) inhibited NE transport and reduced plasma membrane expression of NET and NK1R. Pretreatment with the NK1R antagonist, EMEND (aprepitant) prevented these NK1R-mediated effects. Immunoprecipitation experiments showed that NET forms stable complexes with NK1R. In HTR cells, combined biotinylation and immunoprecipitation studies revealed plasma membrane localization of NET·NK1R complexes. Receptor activation resulted in the internalization of NET·NK1R complexes. Lipid raft and immunoprecipitation analyses revealed the presence of NET·NK1R complexes exclusively in non-raft membrane fractions under basal/unstimulated conditions. However, NK1R activation led to translocation of NET·NK1R complexes to raft-rich membrane fractions. Importantly, PKCα was found in association with raft-localized NET following SP treatment. Similar to WT-NET, PKC-resistant NET-DM was found in association with NK1R exclusively in non-raft fractions. However, SP treatment failed to translocate NET-DM·NK1R complexes from non-raft fractions to raft fractions. Collectively, these results suggest that NK1R forms physical complexes with NET and that the receptor-mediated Thr258 + Ser259 motif-dependent translocation of NET·NK1R complexes into raft-rich microdomains facilitates NET/NK1R interaction with PKCα to coordinate spatially restricted NET regulation. 相似文献
44.
Jung-eun Park Chiman Song Keehyun Choi Taebo Sim Bongjin Moon Eun Joo Roh 《Bioorganic & medicinal chemistry letters》2013,23(20):5515-5518
A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC50 = 14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM–85.6 nM) for three transporters. 相似文献
45.
Sarel J. Robinson Jacobus P. Petzer Anél Petzer Jacobus J. Bergh Anna C.U. Lourens 《Bioorganic & medicinal chemistry letters》2013,23(17):4985-4989
The validity of the chalcone scaffold for the design of inhibitors of monoamine oxidase has previously been illustrated. In a systematic attempt to investigate the effect of heterocyclic substitution on the monoamine oxidase inhibitory properties of this versatile scaffold, a series of furanochalcones were synthesized. The results demonstrate that these furan substituted phenylpropenones exhibited moderate to good inhibitory activities towards MAO-B, but showed weak or no inhibition of the MAO-A enzyme. The most active compound, 2E-3-(5-chlorofuran-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one, exhibited an IC50 value of 0.174 μM for the inhibition of MAO-B and 28.6 μM for the inhibition of MAO-A. Interestingly, contrary to data previously reported for chalcones, these furan substituted derivatives acted as reversible inhibitors, while kinetic analysis revealed a competitive mode of binding. 相似文献
46.
Hye Ri Park Jiyoon Kim Taekeun Kim Seonmi Jo Miyoung Yeom Bongjin Moon Il Han Choo Jaeick Lee Eun Jeong Lim Ki Duk Park Sun-Joon Min Ghilsoo Nam Gyochang Keum C. Justin Lee Hyunah Choo 《Bioorganic & medicinal chemistry》2013,21(17):5480-5487
In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R1 amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5 nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5 nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. 相似文献
47.
Kevin Lewellyn Dobroslawa Bialonska Melissa J. Loria Stephen W. White Kenneth J. Sufka Jordan K. Zjawiony 《Bioorganic & medicinal chemistry》2013,21(22):7083-7090
Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model. 相似文献
48.
《Bioorganic & medicinal chemistry》2013,21(23):7406-7417
A series of Tacrine–Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood–brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer’s disease (AD). 相似文献
49.
Guili Huang Fei Zhu Yuhang Chen Shiqiang Chen Zhonghong Liu Xin Li Linlin Gan Li Zhang Yu Yu 《Analytical biochemistry》2016
A simple, rapid and reliable spectrophotometry was developed to determine monoamine oxidase (MAO). In this study, 2,4-dinitrophenylhydrazine (DNPH), a classic derivatizing reagent, was used to detect MAO-dependent aldehyde production; and traditional DNPH spectrophotometry was simplified. Benzylamine and serotonin oxidation were catalyzed by MAO-B and MAO-A, respectively, to aldehydes. These were derivatized with DNPH, and the corresponding quinones were further formed by adding NaOH. These DNPH derivatives with large conjugated structures were directly measured spectrophotometrically at 465 nm and 425 nm, without the need for precipitating, washing and suspending procedures. The addition of NaOH caused a red shift of the maximum absorption wavelength of these derivatives, which reduced the interference of free DNPH. MAO-B protein was as low as 47.5 μg in rat liver with correlation coefficients ranging within 0.995–0.999. This method is 2–3 times more sensitive than direct spectrophotometry. The detection of MAO inhibition through this method showed that IC50 values of rasagiline are 8.00 × 10−9 M for MAO-B and 2.59 × 10−7 M for MAO-A. These results are similar to the values obtained by direct spectrophotometry. Our study suggests that DNPH spectrophotometry is suitable to detect MAO activity, and has the potential for MAO inhibitor screening in the treatment of MAO-mediated diseases. 相似文献
50.
Anton Shetnev Angelina Osipyan Sergey Baykov Alexander Sapegin Zhanna Chirkova Michail Korsakov Anél Petzer Idalet Engelbrecht Jacobus P. Petzer 《Bioorganic & medicinal chemistry letters》2019,29(1):40-46
Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N-arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50?=?0.012?µM) being the most potent MAO-B inhibitor, while compound 9d (IC50?=?0.751?µM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer’s disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site. 相似文献