Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands

A novel synthetic approach towards N1-alkylated 3-propyl-1,4-benzodiazepines was developed in five synthetic steps from 2-amino-4-chlorobenzophenone, in which the N-oxide 4 served as a key intermediate. The structure-activity relationship optimization of this 3-prophyl-1,4-benzodiazepine template was carried out on the N1-position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N-allyl-3-propyl-benzodiazepine 6d displayed an affinity towards the CCK2 (CCK-B) receptor of 170 nM in a radiolabelled receptor-binding assay. The anxiolytic activity of this allyl-3-propyl-1,4-benzodiazepine 6d was subsequently determined in in-vivo psychotropic assays. This novel ligand had ED50 values of 4.7 and 5.2 mg kg-1 in the black and white box test and the x-maze, respectively, and no significant sedation/muscle relaxation was observed.

X-ray crystallographic and theoretical studies of an anticonvulsant enaminone:methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate

Objective: The aims of this study were to establish the structure of the potent anticonvulsant enaminone methyl 4-(4′-bromophenyl)amino-6-methyl-2- oxocyclohex-3-en-1-oate (E139), and to determine the energetically preferred conformation of the molecule, which is responsible for the biological activity. Materials and Methods: The structure of the molecule was determined by X-ray crystallography. Theoretical ab initio calculations with different basis sets were used to compare the energies of the different enantiomers and to other structurally related compounds. Results: The X-ray crystal structure revealed two independent molecules of E139, both with absolute configuration C11(S), C12(R), and their inverse. Ab initio calculations with the 6-31G, 3-21G and STO-3G basis sets confirmed that the C11(S), C12(R) enantiomer with both substituents equatorial had the lowest energy. Compared to relevant crystal structures, the geometry of the theoretical structures shows a longer C-N and shorter C=O distance with more cyclohexene ring puckering in the isolated molecule. Conclusion: Based on a pharmacophoric model it is suggested that the enaminone system HN-C=C-C=O and the 4-bromophenyl group in E139 are necessary to confer anticonvulsant property that could lead to the design of new and improved anticonvulsant agents. Copyright © 2003 S. Karger AG, Basel.

Phakometric measurement of ocular surface radii of curvature, axial separations and alignment in relaxed and accommodated human eyes

Measurements (autokeratometry, A-scan ultrasonography and video ophthalmophakometry) of ocular surface radii, axial separations and alignment were made in the horizontal meridian of nine emmetropes (aged 20-38 years) with relaxed (cycloplegia) and active accommodation (mean ± 95% confidence interval: 3.7 ± 1.1 D). The anterior chamber depth (-1.5 ± 0.3 D) and both crystalline lens surfaces (front 3.1 ± 0.8 D; rear 2.1 ± 0.6 D) contributed to dioptric vergence changes that accompany accommodation. Accommodation did not alter ocular surface alignment. Ocular misalignment in relaxed eyes is mainly because of eye rotation (5.7 ± 1.6° temporally) with small amounts of lens tilt (0.2 ± 0.8° temporally) and decentration (0.1 ± 0.1 mm nasally) but these results must be viewed with caution as we did not account for corneal asymmetry. Comparison of calculated and empirically derived coefficients (upon which ocular surface alignment calculations depend) revealed that negligible inherent errors arose from neglect of ocular surface asphericity, lens gradient refractive index properties, surface astigmatism, effects of pupil size and centration, assumed eye rotation axis position and use of linear equations for analysing Purkinje image shifts. © 2004 The College of Optometrists.

Continuous measurement of accommodation in human factor applications

It has long been sought to measure ocular accommodation continuously in human factor applications such as driving or flying. Open-field autorefractors such as the Canon R-1 could be converted to allow continuous, objective recording, but steady eye fixation and head immobilisation were essential for the measurements to be valid. Image analysis techniques utilised by newer open-view autorefractors such as the Shin-Nippon SRW-5000 are more tolerant to head and eye movements, but perhaps the technique with the greatest potential for the measurement of accommodation in human factor applications is photoretinoscopy. This paper examines the development of techniques for high temporal measurements of accommodation and reports on the tolerance of one such recent commercial instrument, the PowerRefractor (PlusOptiX). The instrument was found to be tolerant to eye movements from the optical axis of the instrument (∼0.50 DS change in apparent accommodation with gaze 25° eccentric to the optical axis), longitudinal head movement (<0.25 DS from 8 cm towards and 20 cm away from the correct photorefractor to eye distance) and changes in background illuminance (<0.25 DS from 0.5 to 20 cd m-2 target luminance). The PowerRefractor also quantifies the direction of gaze and pupil size, but is unable to take measurements with small pupils <3.7 ±1.0 mm. © 2002 The College of Optometrists.

An assessment of the accuracy of electrolyte concentrations in neonatal parental nutrition

Focal points Over a six-week period in January and February 2002, 2ml samples were removed from all neonatal PN bags dispensed Samples were submitted for analysis of sodium, potassium and magnesium in triplicate by the hospital's clinical chemistry department using a Vitros Codac 950AT, dry slide, automated analyser Only 19.3, 7.1 and 30.4 per cent of measured sodium, potassium and magnesium concentrations respectively deviated by £5 per cent from stated bag concentrations The results indicate that it is possible that some electrolyte concentrations included in neonatal PN vary significantly from stated values