- Benzomorphan skeleton, a versatile scaffold for different targets: A comprehensive review. [Review]
- EJEur J Med Chem 2018 Jun 07; 155:492-502
- Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as ...
Despite the fact that the benzomorphan skeleton has mainly been employed in medicinal chemistry for the development of opioid analgesics, it is a versatile structure. Its stereochemistry, as well as opportune modifications at the phenolic hydroxyl group and at the basic nitrogen, play a pivotal role addressing the benzomorphan-based compounds to a specific target. In this review, we describe the structure activity-relationships (SARs) of benzomorphan-based compounds acting at sigma 1 receptor (σ1R), sigma 2 receptor (σ2R), voltage-dependent sodium channel, N-Methyl-d-Aspartate (NMDA) receptor-channel complex and other targets. Collectively, the SARs data have highlighted that the benzomorphan nucleus could be regarded as a useful template for the synthesis of drug candidates for different targets.
- Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18. [Journal Article]
- EJEur J Med Chem 2018 Jun 01; 155:381-397
- GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases a...
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB1 and CB2) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones with long alkyl chains (optimal length: hexamethylene) efficiently blocked GPR18 with similarly high potency as lead structure 5. (Z)-2-(3-(6-(4-Chlorophenoxy)hexyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB-27, 23) exhibited the best profile: it displayed an IC50 value of 650 nM at GPR18 and showed improved selectivity versus CB receptors as compared to lead structure 5. Importantly, in contrast to 5, which showed only partial inhibition (60%), 23 led to a complete blockade of THC-induced GPR18 activation and is thus a superior tool for target validation. In addition, several compounds, e.g. 18 and 22, were identified as dual GPR18/GPR55 antagonists with similar potency at both targets, and selectivity versus CB receptors.
- Age- and Sex-Related Differences in Motor Performance During Sustained Maximal Voluntary Contraction of the First Dorsal Interosseous. [Journal Article]
- FPFront Physiol 2018; 9:637
- Age and sex affect the neuromuscular system including performance fatigability. Data on performance fatigability and underlying mechanisms in hand muscles are scarce. Therefore, we determined the eff...
Age and sex affect the neuromuscular system including performance fatigability. Data on performance fatigability and underlying mechanisms in hand muscles are scarce. Therefore, we determined the effects of age and sex on force decline, and the mechanisms contributing to force decline, during a sustained isometric maximal voluntary contraction (MVC) with the index finger abductor (first dorsal interosseous, FDI). Subjects (n = 51, age range: 19-77 years, 25 females) performed brief and a 2-min sustained MVC with the right FDI. Abduction force and root mean squared electromyographic activity (rms-EMG) were recorded in both hands. Double-pulse stimulation was applied to the ulnar nerve during (superimposed twitch) and after (doublet-force) the brief and sustained MVCs. Compared to females, males were stronger (134%, p < 0.001) and exhibited a greater decline in voluntary (difference: 8%, p = 0.010) and evoked (doublet) force (difference: 12%, p = 0.010) during and after the sustained MVC. Age did not affect MVC, force decline and superimposed twitch. The ratio between the doublet- and MVC-force was greater in females (0.33, p = 0.007) and in older (0.38, p = 0.06) individuals than in males (0.30) and younger (0.30) individuals; after the sustained MVC this ratio increased with age and the increase was larger for females compared to males (p = 0.04). The inadvertent contralateral, left force and rms-EMG activity increased over time (2.7-13.6% MVC and 5.4-17.7% MVC, respectively). Males had higher contralateral forces than females (p = 0.012) and contralateral force was higher at the start of the contralateral contraction in older compared with young subjects (difference: 29%, p = 0.008). In conclusion, our results suggest that the observed sex-differences in performance fatigability were mainly due to differences in peripheral muscle properties. Yet the reduced amount of contralateral activity and the larger difference in evoked versus voluntary force in female subjects indicate that sex-differences in voluntary activation should not be overlooked. These data obtained in neurological healthy adults provides a framework and help the interpretation and referencing of neurophysiological measures in patients suffering from neuromuscular diseases, who often present with symptoms of performance fatigability.
- New species of Eurycletodes Sars, 1909 and Odiliacletodes Soyer, 1964 from the deep Gulf of California (Copepoda, Harpacticoida, Argestidae). [Journal Article]
- ZZookeys 2018; (764):1-25
- To date, three species of the family Ancorabolidae, three species of the family Argestidae, and one species of the family Rhizothrichidae are known from the deep sea of the Gulf of California. The de...
To date, three species of the family Ancorabolidae, three species of the family Argestidae, and one species of the family Rhizothrichidae are known from the deep sea of the Gulf of California. The descriptions of two new species, Eurycletodes paraephippigersp. n. and Odiliacletodes secundussp. n. collected from the Southern Trough of Guaymas Basin at 1440 m and 1642 m depths, respectively, are presented herein. The closest relatives of these two species, E. ephippiger Por, 1964 and O. gracilis Soyer, 1964 are known from the Mediterranean, but some relatives have been reported also from the southern Atlantic. Eurycletodes paraephippigersp. n. is undoubtedly related to E. ephippiger Por, 1964 known from Israel and Banyuls-sur-Mer (France). These two species can be separated by the armature complement of the basis of the maxillule, by the armature complement of the syncoxa of the maxilliped, and by the relative position of the anal operculum. Odiliacletodes secundussp. n. showed to be closely related to O. gracilis Soyer, 1964 known from Banyuls-sur-Mer only. The latter two species can be separated by the armature complement of the syncoxa of the maxilliped, by the structure of the antenna, and by the inner armature complement of the third exopodal segment of the fourth swimming leg.
- A Rapid and Specific Assay for the Detection of MERS-CoV. [Journal Article]
- FMFront Microbiol 2018; 9:1101
- Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that can cause human respiratory disease. The development of a detection method for this virus that can lead to ra...
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that can cause human respiratory disease. The development of a detection method for this virus that can lead to rapid and accurate diagnosis would be significant. In this study, we established a nucleic acid visualization technique that combines the reverse transcription loop-mediated isothermal amplification technique and a vertical flow visualization strip (RT-LAMP-VF) to detect the N gene of MERS-CoV. The RT-LAMP-VF assay was performed in a constant temperature water bath for 30 min, and the result was visible by the naked eye within 5 min. The RT-LAMP-VF assay was capable of detecting 2 × 101 copies/μl of synthesized RNA transcript and 1 × 101 copies/μl of MERS-CoV RNA. The method exhibits no cross-reactivities with multiple CoVs including SARS-related (SARSr)-CoV, HKU4, HKU1, OC43 and 229E, and thus exhibits high specificity. Compared to the real-time RT-PCR (rRT-PCR) method recommended by the World Health Organization (WHO), the RT-LAMP-VF assay is easy to handle, does not require expensive equipment and can rapidly complete detection within 35 min.
- Insight into the evolution of nidovirus endoribonuclease based on the finding that Nsp15 from porcine deltacoronavirus functions as a dimer. [Journal Article]
- JBJ Biol Chem 2018 Jun 10
- Nidovirus endoribonucleases (NendoUs) include Nsp15 from coronaviruses and Nsp11 from arteriviruses, both of which have been reported to participate in the viral replication process and in the evasio...
Nidovirus endoribonucleases (NendoUs) include Nsp15 from coronaviruses and Nsp11 from arteriviruses, both of which have been reported to participate in the viral replication process and in the evasion of the host immune system. Results from a previous study of coronaviruses SARS-CoV, HCoV-229E and MHV Nsp15 indicate that it mainly forms a functional hexamer, whereas Nsp11 from the arterivirus PRRSV is a dimer. Here, we found that porcine deltacoronavirus (PDCoV) Nsp15 primarily exists as dimers and monomers in vitro. Biological experiments reveal that a PDCoV Nsp15 mutant lacking the first 27 amino acids of the N-terminal domain (NTD, Asn-1-Asn-27) forms more monomers and displays decreased enzymatic activity, indicating that this region is important for its dimerization. Moreover, multiple sequence alignments and three-dimensional structural analysis indicated that the C-terminal region (His-251-Val-261) of PDCoV Nsp15 is 10 amino acids shorter and forms a shorter loop than that formed by the equivalent sequence (Gln-259-Phe-279) of SARS-CoV Nsp15. This result may explain why PDCoV Nsp15 failed to form hexamers. We speculate that NendoUs may have originated from XendoU endoribonucleases (XendoUs) forming monomers in eukaryotic cells and that NendoU from arterivirus gained ability to form dimers and that the coronavirus variants then evolved the capacity to assemble into hexamers. We further propose that PDCoV Nsp15 may be an intermediate in this evolutionary process. Our findings provide a theoretical basis for improving our understanding of NendoU evolution and offer useful clues for designing drugs and vaccines against nidoviruses.
- 3-Benzyl(phenethyl)-2-thioxobenzo[g]quinazolines as a new class of potent α-glucosidase inhibitors: synthesis and molecular docking study. [Journal Article]
- FMFuture Med Chem 2018 Jun 08
- CONCLUSIONS: A new class of potent α-glucosidase inhibitors was identified, and the molecular docking predicted plausible binding interaction of the targets in the binding pocket of α-glucosidase and rationalized the structure-activity relationship (SARs) of the target compounds.
- Aminoacyl-tRNA synthetase deficiencies in search of common themes. [Journal Article]
- GMGenet Med 2018 Jun 06
- CONCLUSIONS: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.
- Nasal priming by a murine coronavirus provides protective immunity against lethal heterologous virus pneumonia. [Journal Article]
- JIJCI Insight 2018 Jun 07; 3(11)
- The nasal mucosa is an important component of mucosal immunity. Immunogenic particles in inspired air are known to activate the local nasal mucosal immune system and can lead to sinonasal inflammatio...
The nasal mucosa is an important component of mucosal immunity. Immunogenic particles in inspired air are known to activate the local nasal mucosal immune system and can lead to sinonasal inflammation; however, little is known about the effect of this activation on the lung immune environment. Here, we showed that nasal inoculation of murine coronavirus (CoV) in the absence of direct lung infection primes the lung immune environment by recruiting activated monocytes (Ly6C+ inflammatory monocytes) and NK cells into the lungs. Unlike infiltration of these cells into directly infected lungs, a process that requires type I IFN signaling, nasally induced infiltration of Ly6C+ inflammatory monocytes into the lungs is IFN-I independent. These activated macrophages ingested antigen and migrated to pulmonary lymph nodes, and enhanced both innate and adaptive immunity after heterologous virus infection. Clinically, such nasal-only inoculation of MHV-1 failed to cause pneumonia but significantly reduced mortality and morbidity of lethal pneumonia caused by severe acute respiratory syndrome CoV (SARS-CoV) or influenza A virus. Together, the data indicate that the nose and upper airway remotely prime the lung immunity to protect the lungs from direct viral infections.
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- Making head or tail of cnidarian hox gene function. [Journal Article]
- NCNat Commun 2018 Jun 05; 9(1):2187
- Distantly related animals have spectacularly different shapes and body plans, which can render it difficult to understand which of their body parts may have a shared evolutionary origin. Studying the...
Distantly related animals have spectacularly different shapes and body plans, which can render it difficult to understand which of their body parts may have a shared evolutionary origin. Studying the molecular regulation of the development of these body parts during embryogenesis can help identifying commonalities that are not visible by eye.