N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.     

Synthesis and antimicrobial activity of 7 beta-[N-(arylmethyloxyimino) acetamido]cephalosporanic acid derivatives

Some cephalosporanic acid derivatives substituted on the C(7) amino nitrogen with (arylmethyloxyimino)acetyl moieties were synthesized and tested in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria. The new compounds showed a modest activity directed only against Gram positive microorganisms.     

新型间硝基苯甲酸稀土配位聚合物[Nd2(C7H4O4N)7(H2O)4]n的水热合成和晶体结构

采用水热方法合成出一种新型的间硝基苯甲酸稀土配位聚合物[Nd2(C7H4O4N)7H2O]n,并通过元素分析、红外光谱、X射线单晶结构分析对该配位聚合物进行了表征.标题配位聚合物的晶体属于三斜晶系,P1空间群,晶胞参数a=0.9848(2)nn,b=1.131 4(2)nm,c=1.366 3(3)nm,α=69.22(3).,β=82.48(3).,γ=82.21(3).,V=1.4045(5)nm3,Dc=1.806g/cm3,Z=1.结构分析表明:标题化合物是由稀土金属Nd(Ⅲ)和间硝基苯甲酸组成的配位聚合物,此聚合物通过Ln-O-C-O-Ln形成无限一维链状结构,进一步又通过分子间氢键连接形成复杂的三维氢键网络结构.     

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602)

A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.     

N-[4-(1,1''-biphenyl)methyl]-4-(4-thiomorpholinylmethyl) benzenamines as non-oxazolidinone analogues of antimycobacterial U-100480

Twenty-three patients underwent conventional arteriography and 3D contrast enhanced magnetic resonance angiography explorations. The study was limited to the iliofemoral arteries (13 segments for each patient). Each segment was classified as having 0-49%, 50-99% or 100% stenosis. Overall results were excellent with K = 0.822, sensitivity 92% and specificity 93%. Segment by segment analysis corroborated the overall results except for the internal iliac arteries and the deep femoral arteries, demonstrating the limitations of this technique in this series.     

Characterization of the neurochemical effects of N-[2-(1-azabicyclo[3,3,0]octan-5-yl)ethyl]2-nitroaniline fumarate (SK-946) as a cognition activator

BACKGROUND: This study characterized the phenotypic subsets of isolated gastric lymphocytes and the cellular immune response in cultured gastric biopsy specimens. METHODS: Endoscopy specimens from 40 Helicobacter pylori-positive and 40 H. pylori-negative patients were studied. a) Isolated gastric lymphocytes were analysed for CD4+, CD8+ T-lymphocyte subsets, activated T cells, and natural killer cells on a fluorescence-activated cell sorter, using monoclonal antibodies. b) The supernatant of cultured gastric biopsy specimens were assayed for interleukin (IL)-2, IL-4, and IL-6 levels. RESULTS: In H. pylori-positive patients there was (a) a decrease in CD4+/CD8+ T cells, no change in activated T cells, and an increase in natural killer cells, and (b) no change in IL-2 levels and a significant increase in IL-4 and IL-6 levels. CONCLUSIONS: There is an increase in CD8+ lymphocytes and natural killer cells, and the observed increase in IL-4 and IL-6 might be important in H. pylori-associated gastritis.     

Synthesis and antitumor activity of 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates

Ten 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates were synthesized and evaluated for antitumor activity. The 2-phenoxyethyl ester exhibited activity against P-388 lymphocytic leukemia, and the n-butyl and n-pentyl esters exhibited activity against L-1210 lymphoid leukemia in initial screening tests.     

Evaluation of 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose, a new fluorescent derivative of glucose, for viability assessment of yeast Candida albicans

A new fluorescent derivative of D-glucose, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), which had been previously developed for the analysis of glucose uptake activity by living cells, was investigated to evaluate its applicability for assaying the viability of yeast Candida albicans. Lineweaver-Burk plots showed to uptake of 2-NBDG to be competitively inhibited by D-glucose and not by L-glucose, which suggested the involvement of the glucose transporting system of C. albicans in the uptake of 2-NBDG. A good correlation was obtained between the yeast viability, determined by the plate-count method, and the 2-NBDG uptake activity of yeast cells (correlation constant: r = 0.97). This is expected to lead to the development of a new fluorescent probe for the determination of yeast cell viability.     

Serotonin 5-HT4 receptor agonistic activity of the optical isomers of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide

OBJECTIVE: To compare the influence of incongruent (asymmetric) follicular development on treatment outcome in IVF-ET and GIFT cycles. DESIGN: A retrospective comparative study. SETTING: Tertiary referral center for infertility. PATIENT(S): Five hundred forty-three consecutive assisted reproduction cycles (428 IVF-ET and 115 GIFT) in 422 infertile patients. INTERVENTION(S): Controlled ovarian hyperstimulation (COH) and IVF-ET or GIFT. MAIN OUTCOME MEASURE(S): The incongruity ratio as a parameter of the asymmetry in follicular development and pregnancy rate (PR). RESULT(S): For GIFT cycles, the PRs were 37.8% and 15.7% in cycles with congruent and incongruent follicular development, respectively. However, for IVF-ET cycles, the PR was not affected by incongruent follicular development: 28.2% and 29.0%, respectively. An inverse relationship was observed between the degree of incongruity and the estimated probability of pregnancy in GIFT cycles but not in IVF-ET cycles. Neither the side of the dominant ovary nor the degree of incongruity were consistent in consecutive cycles. CONCLUSION(S): Incongruent follicular development during COH has a significantly negative influence on the outcome of GIFT cycles but not on the outcome of IVF-ET cycles. The reason for this difference is not clear. We recommend considering IVF-ET instead of GIFT if incongruent follicular development occurs.     

Synthesis and Characterization of Some Lanthanide（Ⅲ） Complexes with 4- [N-（2-methoxy benzylinine）formy1]-2, 3-dimethyl-1-phenyl-3-pyazolin-5-one

A series of seven novel lanthanide（Ⅲ ） nitrato complexes with 4-[ N-（2-methoxybenzylimine）formyl] 1-2, 3- dimethyl-1-phenyl-3-pyazolin-5-one （2mbfa）, were synthesized. These complexes were characterized by elemental analysis, molecular mass determination, conductance and magnetic moment measurements, IR, UV-visible, and ^13CNMR spectral studies, In these complexes, the Schiff base, 2mbfa, acts as neutral bidentate ligand by utilizing the carbonyl oxygen and azomethine nitrogen as donor sites. All the three nitrate ions are also coordinated unidentately with 7 coordination for the lanthanide（Ⅲ） ions with a tentative monocapped octahedral geometry for the complexes. All the seven lanthanide（Ⅲ） complexes have a general formula, [ Ln（2mbfa）：（NO3）3 ].     

新显色剂2-苯并噻唑偶氮-7-(4-羧基苯偶氮)-变色酸的合成及与铁显色反应研究

合成了一种新的杂环不对称双偶氮变色酸试剂 2-苯并噻唑偶氮-7-( 4-羧基苯偶氮 )-变色酸 (简称BTACPACA)。研究了试剂的结构和光度性质 ,结果表明 :在 pH6.0～ 6.4的缓冲介质中 ,Fe 与BTACPACA及CTMAB形成 1∶2∶1的三元络合物 ,其最大吸收波长为 685nm ,表观摩尔吸光系数ε =1.13× 10 5,在 2 5mL溶液中 0～ 6μg范围内Fe 符合比尔定律。建立了测定石灰石和高炉渣中铁的新方法 ,结果满意。     

Synthesis and Crystal Structure of a Neodymium Ionic Associate [Nd(dmso)7Cl][Bph4]2

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新显色剂2-苯并噻唑偶氮-7-(4-羧基苯偶氮)-变色酸的合成及与铁(Ⅲ)显色反应研究

合成了一种新的杂环不对称双偶氮变色酸试剂2-苯并噻唑偶氮-7-(4-羧基苯偶氮)-变色酸(简称BTACPACA).研究了试剂的结构和光度性质,结果表明在pH6.0～6.4的缓冲介质中,Fe(Ⅲ)与BTACPACA及CTMAB形成1∶2∶1的三元络合物,其最大吸收波长为685nm,表观摩尔吸光系数ε＝1.13×105,在25mL溶液中0～6μg范围内Fe(Ⅲ)符合比尔定律.建立了测定石灰石和高炉渣中铁的新方法,结果满意.     

Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (I) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.8, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SERT site.     

New types of synthetic infusion solutions. III. Elimination and retention of poly-[N-(2-hydroxypropyl)methacrylamide] in a test organism

The elimination and retention of a new, fully synthetic plasma prosthesis of Czechoslovak origin under the working name of Duxon (poly[N-(2-hydroxypropyl)methacrylamide]) was investigated in experiments on rabbits by using a 14C-labeled polymer. Results published earlier on elimination have been confirmed and extended. Retention was examined after repeated application. The effect of molecular weight prevailed both in elimination and in retention. Polymers of lower molecular weights, which possess a good therapeutical effect, are not permanently deposited in the organism.     

Design, synthesis and quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine derivatives as potent Na/H exchange inhibitors

Recent results indicate that a fluoroalumino complex (AlFx) is probably the molecule responsible for the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells. Initial analysis suggested that a tyrosine phosphorylation (tyr phos) process similar to that induced by thrombin and activation of the p42 MAP kinase (ERK 2) mediate this cellular response. In the present study, the signaling mechanism activated by AlFx was further investigated. The results indicated that AlFx dose-dependently enhanced the tyr phos of the cell adhesion proteins FAK and paxillin, as well as of the adaptor molecules p46shc, p52shc, and p66shc and their association with GRB2. Pretreatment of MC3T3-E1 cells with cytochalasin D completely prevented FAK and paxillin tyr phos without any alteration in the tyr phos of Shc proteins and activation of ERK2 induced by AlFx. This observation suggests that in confluent MC3T3-E1 cells, there is no link between the activation of FAK induced by AlFx and the stimulation of ERK2. Pretreatment of the cells with pertussis toxin inhibited Shc phosphorylation, activation of ERK2, and markedly reduced cell replication induced by AlFx. This toxin also significantly reduced the stimulation of Pi transport activity induced by AlFx in these cells. Alteration in tyr phos induced by AlFx was not associated with any detectable inhibition of tyrosine phosphatase activity in MC3T3-E1 cell homogenates, suggesting that enhanced tyr phos induced by AlFx probably resulted from activation of a tyrosine kinase. In conclusion, the results of this study suggest that the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells is mediated by the activation of a pertussis toxin-sensitive Gi/o protein and suggest an important role for these heterotrimeric G proteins in controlling the growth and differentiation of bone-forming cells.