4-(Phenoxy)pyridin-3-yl]methylamines: a new class of selective noradrenaline reuptake inhibitors

[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.     

Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists

Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT_1A) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT_1A partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.     

Design,synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT_1A partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT_1A partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.     

Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors

A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.     

Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists

Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1_A partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT_1A receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1_A partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT_1A in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.     

Design,synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more polar template

Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Structure–activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenyl ring; consequently, selective NRIs and dual NSRIs were prepared. Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic (Δclog P ?0.9).     

Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition

Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.     

Cloning of a nitrate reductase inactivator (NRI) cDNA from <Emphasis Type="Italic">Spinacia oleracea</Emphasis> L. and expression of mRNA and protein of NRI in cultured spinach cells

The spinach ( Spinacia oleracea L. (cv. Hoyo) nitrate reductase inactivator (NRI) is a novel protein that irreversibly inactivates NR. Using degenerate primers based on an N-terminal amino acid sequence of NRI purified from spinach leaves and a cDNA library, we isolated a full-length NRI cDNA from spinach that contains an open reading frame encoding 479 amino acid residues. This protein shares 67.4% and 51.1-68.3% amino acid sequence similarities with a nucleotide pyrophosphatase (EC 3.6.1.9) from rice and three types of the nucleotide pyrophosphatase-like protein from Arabidopsis thaliana, respectively. Immunoblot analysis revealed that NRI was constitutively expressed in suspension-cultured spinach cells; however, its expression level is quite low in 1-day-subcultured cells. Moreover, northern blot analysis indicated that this expression was regulated at the mRNA level. These results suggest that NRI functions in mature cells.     

Broadband Mid-infrared Dual-Band Double-Negative Metamaterial: Realized Using a Simple Geometry

We design and numerically demonstrate a novel metamaterial structure consisting of a dielectric layer sandwiched between two silver films and is perforated with two kinds of square-shaped holes at different angles, which is a dual-band double-negative (each band possesses simultaneously negative permittivity and permeability) metamaterial with broad NRI bands in mid-infrared region(3–30 μm). The broadband of NRI contributed to the strong magnetic resonance caused by the excitation of surface plasmon polaritons. The influence of the number of square-shaped holes on the properties of the designed structures are also investigated by analyzing and comparing the transmission, permeability, permittivity, refractive index, and figure of merit. Then, by optimizing the structural parameters, the proposed structure exhibits a negative band with a figure of merit of 3.3, which is to our knowledge larger than previously reported plasmonic metamaterial in mid-infrared region(M-IR). The value of negative refractive index(NRI) reaches −6 and the bandwidth of NRI can reach up to 4.2 THz in the low-frequency band of M-IR region, which is the widest NRI band in M-IR spectrum at present as far as we know. Moreover, the metamaterial structure is simple and easy to be manufactured with standard fabrication techniques. This work will be very meaningful in designing dual-band negative-index material with broad NRI band and low loss. Finally, the proposed metamaterial has huge potential applications in multiband or broadband devices.

     

Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine as selective noradrenaline reuptake inhibitors: Reducing P-gp mediated efflux by modulation of H-bond acceptor capacity

Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.     

Novel inhibitors of bacterial protein synthesis: structure-activity relationships for 1,8-naphthyridine derivatives incorporating position 3 and 4 variants

Structure-activity relationships for a recently discovered novel ribosome inhibitor (NRI) class of antibacterials were investigated. Preliminary efforts to optimize protein synthesis inhibitory activity of the series through modification of positions 3 and 4 of the naphthyridone lead template resulted in the identification of several biochemically potent analogues. A lack of corresponding whole cell antibacterial activity is thought to be a consequence of poor cellular penetration as evidenced by the enhancement of activity observed for a lead analogue tested in the presence of a cell permeabilizing agent.     

物种谱系不确定性对群落谱系格局指标的影响

物种谱系关系常被用于衡量群落谱系格局及推断格局背后的生态过程,但多数研究往往忽视谱系关系的不确定性及其可能对群落谱系格局造成的影响.为此,本文以浙江天童20 hm^2样地内150个树种为研究对象,采用这些物种叶绿体DNA的rbcL和matK碱基序列构建1棵一致系统发育树和反映谱系不确定性的999棵系统发育树,然后结合样地物种分布数据计算标准化净亲缘指数(NRI)和最近亲缘指数(NTI),最后运用独立置换零模型衡量样地群落谱系格局.结果表明:物种系统发育树在拓扑结构和物种谱系分支节点年龄上均存在较大的不确定性,谱系不确定性随着谱系分支节点年龄的减小而增大,也随物种间平均谱系距离的增加而增加;在样方尺度上,物种谱系的不确定性增加了标准化NRI和NTI指数的变异,但对两个指数的影响几乎独立;其对两指数的空间分布影响不同,且程度不一,其中标准化NRI受到的影响相对更大;在群落尺度上,物种谱系的不确定性增加了标准化NRI和NTI的变异,平均变异系数分别为0.37和0.077,表明群落水平的标准化NRI更易受到谱系不确定性的影响.这说明物种谱系不确定性会传递到常用的群落谱系格局指标中,且不同指标受影响的程度不同,进而影响对群落谱系格局的衡量及相关生态过程的推断.该结论也暗示以往不考虑谱系不确定性的研究中,非随机的群落谱系格局比例可能被高估.     

2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression

Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.     

Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.     

阿拉善荒漠灌丛群落谱系结构及其影响因子

为探究阿拉善荒漠灌丛群落的构建机制,该研究选取净亲缘关系指数(NRI)作为谱系结构指数,在对阿拉善荒漠灌丛群落野外调查的基础上,以群落物种组成为基础数据,计算各样地群落的NRI,并分析NRI在经纬度梯度上的变化趋势及其与土壤因子和水热因子的关系。结果表明:(1)阿拉善荒漠灌丛群落谱系结构在阿拉善高原东南部以发散状态为主,在阿拉善高原西部和北部地区以聚集状态为主。(2)阿拉善荒漠灌丛群落的NRI随经度的升高而减小,随纬度的升高而增大。(3)阿拉善荒漠土壤质地、土壤容重、土壤pH值和土壤有机碳含量与其群落谱系结构均无显著相关性;在降水因子和温度因子中,与群落谱系结构相关系数最大的分别为年降水量和年温度变化范围(最暖月最高温与最冷月最低温的差值),其中:年降水量与NRI呈显著负相关关系,年温度变化范围与NRI呈显著正相关关系,且最暖月最高温和最冷月最低温与NRI均有显著相关性,推测年温度变化范围对阿拉善灌丛群落谱系结构的影响是通过最暖月最高温和最冷月最低温起作用的。研究发现,阿拉善高原东南部区域的荒漠灌丛群落构成主要受竞争排斥的作用,其西部和北部地区的群落构成主要受环境过滤的影响;阿拉善荒漠灌丛群落的谱系结构主要受年降水量和极端温度的影响。