Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.     

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance.

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Investigating the dopaminergic basis of extraversion in humans: A multilevel approach.

A recent theory suggests that the agency facet of Extraversion (E) is based on brain dopamine (DA). The paucity of human data relevant to this model is probably due to the lack of widely accessible noninvasive psychophysiological indices and well-established behavioral measures sensitive to both E and manipulations of DA activity. Aiming to identify such measures, the authors assessed the electroencephalogram and n-back task performance in groups of introverts and extraverts after administration of either placebo or a selective DA D2 receptor antagonist. As predicted, the antagonist's effects on n-back reaction time measures and frontal versus parietal electroencephalogram theta activity were strongly and specifically modulated by E. New research avenues and theoretical extensions suggested by these results are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mating disruption of pea mothCydia nigricana F. (lepidoptera: Tortricidae) by a repellent blend of sex pheromone and attraction inhibitors

Synthetic sex pheromone of the pea mothCydia nigricana, (E,E)-8,10-dodecadien-1-yl acetate (E8,E10–12: Ac), was applied in polyethylene dispensers at a rate of 30 g/ha and 600 dispensers/ha in a 0.6-ha pea field. The release rate ofE8,E10–12: Ac was 140 mg/ha/day after six days, and 82 mg/ha/day after 20 days. Aerial concentrations ofE8,E10–12: Ac, as measured by a portable EAG apparatus, ranged from 2 ± 2 to 7 ± 3 ng/m³. The antennal signal was high and rather constant within pea canopy, but was lower and fluctuated strongly above canopy. Initially, >99% isomerically pureE8,E10–12: Ac was released, and male moths were attracted to dispensers. After nine days, isomeric blend composition had equilibrated to approx. 92%E8,E10–12: Ac and 8% of the inhibitory isomersE,Z-,Z,E-, andZ8,Z10–12: Ac. Males were then repelled from the pheromone-permeated field. Traps baited with 100 µgE8,E10–12: Ac caught 258 ± 133C. nigricana males/trap in the control, but no males at all in the disruption field.     

Support for (Z)-11-Hexadecanal as a Pheromone Antagonist in Ostrinia nubilalis: Flight Tunnel and Single Sensillum Studies with a New York Population

The flight-tunnel response of male Z-strain European corn borer moths (ECB), Ostrinia nubilalis, from a population in New York State (USA), was significantly antagonized by addition of 1% (Z)-11-hexadecanal (Z11-16:Ald) to their sex pheromone (a 97:3 mix of (Z)- and (E)-11-tetradecenyl acetate [Z/E11-14:OAc]). The level of antagonism was equivalent to that observed for the previously identified ECB antagonist, (Z)-9-tetradecenyl acetate (Z9-14:OAc), and supports a recent report showing that Z11-16:Ald, a minor pheromone component of the Noctuid moth, Sesamia nonagrioides, caused antagonism of ECB pheromone communication in sympatric populations in the Iberian Peninsula. Single-sensillum recordings from ECB antennae, which included cross-adaptation experiments, showed that the same olfactory receptor neuron processing Z9-14:OAc inputs was responsible for detecting Z11-16:Ald, and that this neuron was not responsive to two other aldehydes, (Z)-9-tetradecanal (Z9-14:Ald) and (Z)-9-hexadecanal (Z9-16:Ald), found in other moth sex pheromones. Our results show that the antagonism is not confined to one geographic region, is specific for Z11-16:Ald, and that antagonist pathways might have the potential for processing a number of structurally similar compounds.     

Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is an important part of the cholinergic nerve system in the brain. Moreover, it is associated with a cholinergic anti-inflammatory pathway in the termination of the parasympathetic nervous system. Antagonists of α7 nAChR are a wide group represented by conotoxin and bungarotoxin. Even Alzheimer's disease drug memantine acting as an antagonist in its side pathway belongs in this group. Agonists of α7 nAChR are suitable for treatment of multiple cognitive dysfunctions such as Alzheimer's disease or schizophrenia. Inflammation or even sepsis can be ameliorated by the agonistic acting compounds. Preparations RG3487, SEN34625/WYE-103914, SEN12333, ABT-107, Clozapine, GTS-21, CNI-1493, and AR-R17779 are representative examples of the novel compounds with affinity toward the α7 nAChR. Pharmacological, toxicological, and medicinal significance of α7 nAChR are discussed throughout this paper.     

Biocontrol of Gray Mold Disease on Strawberry Fruit by Integration of Lactobacillus plantarum A7 with Ajwain and Cinnamon Essential Oils

This study was conducted to evaluate the efficacy of the Lactobacillus plantarum A7 (L. Plantarum), ajwain and cinnamon essential oils (AO and CO, respectively) in suppressing gray mold rot in strawberry fruit. AO and CO showed over 90% inhibition of radial mycelia growth with lower concentration of the oils per plate for all tested pathogens. Combined application of L. plantarum with AO and CO was tested to assess the possible synergistic effects of these 3 elements on the control of tested plant pathogens. In this case both combinations of L. plantarum + AO and L. plantarum + CO inhibited the mycelia growth of the pathogens completely. Results showed that the combined treatment of strawberry fruits with L. plantarum + AO (50 μL) and L. plantarum + CO (100 μL) resulted in remarkably improved control of Botrytis infections, in comparison with application of L. plantarum or essential oils alone. Quality attributes (that is pH, acidity, vitamin C, and total soluble solid) of the strawberry fruits did not change significantly (P < 0.01) when combination of Lactobacillus and essential oils was used. To the best of our knowledge, this is the first report on the effects of combination of a Lactobacillus as an antagonist bacterium with essential oils to increase the shelf life of strawberry.     

雷莫司琼降低幼鼠内脏痛觉敏感性

目的: 采用行为学和电生理学评价方法,探讨应用5-羟色胺3(5-HT₃)受体拮抗剂雷莫司琼对幼鼠内脏痛觉敏感性影响。方法: 新生期反复结直肠刺激(colorectal irritation,CI)建立幼鼠内脏痛觉高敏感性模型。32只SD新生大鼠按2×2析因设计分成4组,每组8只,A₁B₁组:新生期反复CI,15~21 d 腹腔注射雷莫司琼;A₁B₂组:新生期反复CI,15~21d 腹腔注射生理盐水;A₂B₁组:新生期未接受CI,15~21 d 腹腔注射雷莫司琼;A₂B₂组:新生期未接受CI,15~21 d 腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),通过观察幼鼠在不同压力结直肠扩张(colorectal distension,CRD)刺激后的腹壁撤退反射(AWR)评分、内脏痛阈和腹外斜肌放电测量进行内脏痛觉敏感性评价。结果: 幼鼠痛阈受建立内脏痛敏化模型和早期雷莫司琼干预两因素影响。建立内脏痛敏化模型可使幼鼠痛阈降低 11.56 mm Hg,早期雷莫司琼干预则使幼鼠痛阈提高 9.06 mm Hg,两者存在交互作用。应用雷莫司琼使AWR评分及腹外斜肌放电幅值降低,对于AWR评分的主效应在各个CRD压力下有统计学意义;对腹外斜肌放电幅值的主效应在各不同CRD压力下亦有统计学意义。结论:应用5?HT3受体拮抗剂雷莫司琼能够降低幼鼠内脏痛觉的高敏感性。     

Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.     

Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P_1-5). Increasing numbers of studies have indicated the importance of S1P₃ in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P₃ receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P₃ selective pepducin agonist) and KRX-722 (an S1P₁-selective pepducin agonist). Those selective towards S1P₃ (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.