Stereoselective stimulus effects of 3-methylflunitrazepam and pentobarbital

Rats trained to discriminate 3.0 mg/kg of diazepam from saline in a two-lever operant choice task were challenged with the racemic mixture and optical isomers of 3- methylflunitrazepam or pentobarbital. Generalization of the diazepam stimulus was found to occur to (+/-)- and S(+)-3- methylflunitrazepam , with the S(+)-isomer being twice as active as the racemate. Diazepam stimulus generalization also occurred to (+/-)-, S(-)-, and R(+)-pentobarbital, with the S(-)-isomer being approximately twice as active as (+/-)- or R(+)-pentobarbital. In addition, the administration of the imidazobenzodiazepine Ro 15-1788, a selective benzodiazepine receptor antagonist, prior to benzodiazepine or barbiturate administration competitively antagonized the discriminative stimulus properties of the benzodiazepines but was completely ineffective in attenuating the discriminative stimulus effect of the barbiturates. The results of this study suggest that benzodiazepines exert their stimulus effects by a stereoselective interaction at a benzodiazepine receptor and that stereochemical factors are important in evaluating the stimulus properties of benzodiazepines or barbiturates.     

Electrical coupling between the human serotonin transporter and voltage-gated Ca channels

Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca²⁺ mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca²⁺ permeability is currently unknown. We investigate the functional interaction between the human serotonin transporter (hSERT) and voltage-gated Ca²⁺ channels (Ca_V). We introduce an excitable expression system consisting of cultured muscle cells genetically engineered to express hSERT. Both 5HT and S(+)MDMA depolarize these cells and activate the excitation-contraction (EC)-coupling mechanism. However, hSERT substrates fail to activate EC-coupling in Ca_V1.1-null muscle cells, thus implicating Ca²⁺ channels. Ca_V1.3 and Ca_V2.2 channels are natively expressed in neurons. When these channels are co-expressed with hSERT in HEK293T cells, only cells expressing the lower-threshold L-type Ca_V1.3 channel show Ca²⁺ transients evoked by 5HT or S(+)MDMA. In addition, the electrical coupling between hSERT and Ca_V1.3 takes place at physiological 5HT concentrations. The electrical coupling between monoamine neurotransmitter transporters and Ca²⁺ channels such as Ca_V1.3 is a novel mechanism by which endogenous substrates (neurotransmitters) or exogenous substrates (like ecstasy) could modulate Ca²⁺-driven signals in excitable cells.     

A preliminary investigation of mesoionic xanthine analogues as inhibitors of platelet aggregation

A series of mesoionic xanthines (e.g. mesoionic thiazolopyrimidines, 3, and thiadiazolopyrimidines, 5) and related analogues were examined as inhibitors of human platelet aggregation. Appropriately substituted compounds were found to fully inhibit platelet aggregation, and anhydro-(6-ethyl-8-isopentyl-7-oxo-5-hydroxy-1,3,4-thiadiazolo[3,2 -a]pyrimidinium hydroxide) (5b) was 40 times more potent than the structurally related xanthine theophylline (1). Gel filtration studies suggest that compound 5b irreversibly inhibits aggregation and this might be due to its ability to act as a latent acylation agent.     

A comparison of the binding of three series of nicotinic ligands

A total of 24 aryl-substituted analogues of nicotine (1a) and two related series of nicotinic ligands, aminomethylpyridines 3 and ether analogues 8, were examined to determine if they bind at alpha4beta2 nACh receptors in a common manner. A modest correlation (r=0.785) was found between the affinities of the nicotine analogues and derivatives of 3, but little correlation (r=0.348) was found with analogues 8. However, a modest correlation (r=0.742) exists between the binding of analogues 3 and 8. It seems that 1-series and 8-series compounds bind differently but that the 3-series compounds share some intermediate binding similarity with both.     

Spatial and temporal expression of surfactant proteins in hyperoxia-induced neonatal rat lung injury

Background

Although personal cigarette smoking is the most important cause and modulator of chronic obstructive pulmonary disease (COPD), secondhand smoke (SHS) exposure could influence the course of the disease. Despite the importance of this question, the impact of SHS exposure on COPD health outcomes remains unknown.

Methods

We used data from two waves of a population-based multiwave U.S. cohort study of adults with COPD. 77 non-smoking respondents with a diagnosis of COPD completed direct SHS monitoring based on urine cotinine and a personal badge that measures nicotine. We evaluated the longitudinal impact of SHS exposure on validated measures of COPD severity, physical health status, quality of life (QOL), and dyspnea measured at one year follow-up.

Results

The highest level of SHS exposure, as measured by urine cotinine, was cross-sectionally associated with poorer COPD severity (mean score increment 4.7 pts; 95% CI 0.6 to 8.9) and dyspnea (1.0 pts; 95% CI 0.4 to 1.7) after controlling for covariates. In longitudinal analysis, the highest level of baseline cotinine was associated with worse COPD severity (4.7 points; 95% CI -0.1 to 9.4; p = 0.054), disease-specific QOL (2.9 pts; -0.16 to 5.9; p = 0.063), and dyspnea (0.9 pts; 95% CI 0.2 to 1.6 pts; p < 0.05), although the confidence intervals did not always exclude the no effect level.

Conclusion

Directly measured SHS exposure appears to adversely influence health outcomes in COPD, independent of personal smoking. Because SHS is a modifiable risk factor, clinicians should assess SHS exposure in their patients and counsel its avoidance. In public health terms, the effects of SHS exposure on this vulnerable subpopulation provide a further rationale for laws prohibiting public smoking.     

Automatic layout and visualization of biclusters

Background  

Biclustering has emerged as a powerful algorithmic tool for analyzing measurements of gene expression. A number of different methods have emerged for computing biclusters in gene expression data. Many of these algorithms may output a very large number of biclusters with varying degrees of overlap. There are no systematic methods that create a two-dimensional layout of the computed biclusters and display overlaps between them.     

Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors

Structure-affinity relationships for the binding of 3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine (AXPQ) at alpha7 nACh receptors were investigated due to its close structural similarity to a known alpha7 antagonist.     

Design,synthesis, and preliminary pharmacological evaluation of new imidazolinones as l-DOPA prodrugs

l-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson’s disease. However, therapy with l-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected l-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of l-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release l-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a–b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a–b and 15a are also reported.