Are Alpha-2D Adrenoceptor Subtypes Involved in Rat Mydriasis Evoked by New Imidazoline Derivatives: Marsanidine and 7-Methylmarsanidine?

The imidazoline compounds may produce mydriasis after systemic administration to some species (rats, cats, and mice). In mydriatic activity of imidazolines, α2D-adrenoceptors subtype(s) seems to be involved. In this study, the pupil dilatory effect evoked by 2 newly synthesized imidazoline derivatives-α2-adrenoceptor agonists: marsanidine and 7-methylmarsanidine-was compared. The compounds were tested alone as well as in the presence of α2-adrenoceptor antagonists (nonselective, yohimbine, and selective toward the following α2-adrenoceptor subtypes-α2A-2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408), α2B-2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239), α2C-JP1302, α2D-2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole hydrochloride [RX821002]). The agonists were studied in male Wistar rats and were administered intravenously in cumulative doses. The antagonistic compounds were given in a single dose before the experiment with marsanidine or 7-methylmarsanidine. Pupil diameter was measured with stereoscopic microscope equipped in green light filter. Marsanidine and 7-methylmarsanidine exerted marked mydriatic effects. BRL44408, JP1302, and ARC239 did not cause significant parallel shift to the right of the dose-effect curves obtained for both imidazolines. In case of yohimbine and RX821002, the marked parallel shifts of dose-response curves were observed, with the antagonistic effects of RX821002 more pronounced. In vivo pharmacodynamics experiment suggests that α2D-adrenoceptor subtype is mainly engaged in mydriatic effects evoked in rats by imidazoline derivatives, in particular by clonidine.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED50 in µmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logkw, were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED50) and logkw values was obtained. The lack of "predictive" QSAR for the whole series of the structurally diverse agents is probably due to a complex mechanism of the ligand-alpha2-adrenergic receptor interactions, which are predominantly of a highly structurally specific polar nature. Such interactions are difficult to quantify with the established chemical structural descriptors, contrary to the less specific, molecular bulkiness-related interactions.

Mydriasis model in rats as a simple system to evaluate α2-adrenergic activity of the imidazol(in)e compounds.

Imidazol(in)e compounds show the diversity of pharmacological effects including mydriasis, hypotension, sedation, bradycardia and hypothermia. At first it was postulated that these effects are mediated via α2-adrenoceptors exclusively. Clonidine is well known as a model agent to produce pupillary dilation in rats. However, it became obvious later that clonidine-like imidazol(in)e adrenoceptor agonists which produced mydriasis in rats, exhibit also a high affinity for imidazoline I1-receptors. That short report attempts to review the present status of studies to confirm that the mydriasis model in rats can be a selective system to evaluate the α2-adrenergic activity of potential pharmacologically active compounds of imidazol(in)e structure.

Factor analysis of microbiological activity data and structural parameters of antibacterial quinolones.

Factor analysis (FA) was performed on quinolone derivatives with antibacterial activity to model relationships between molecular descriptors and microbiological activities determined on five bacterial cell lines (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae). Molecular modeling studies were performed with the use of HyperChem software and MM+ molecular mechanics with the semi-empirical AM1 method. Factor analysis led to the extraction of two main factors, with the share of factor 1 amounting to about 76% and factor 2 to about 24% for all the parameters used in the statistical analysis. Moreover, FA results indicated that energy of orbitals lowest unoccupied molecular orbital, energy of ionization, electron affinity, electronegativity, maximum electron density, refraction and polarizability appeared to be descriptors important for the antibacterial activity of quinolones.

Binding of an oxindole alkaloid from Uncaria tomentosa to amyloid protein (Abeta1-40).

The primary aim of this work was to determine the interactions of an oxindole alkaloid (mitraphylline) isolated from Uncaria tomentosa with beta-amyloid 1-40 (Abeta1-40 protein) applying the capillary electrophoresis (CE) method. Specifically the Hummel-Dreyer method and Scatchard analysis were performed to study the binding of oxindole alkaloids with Abeta1-40 protein. Prior to these studies extraction of the alkaloid of interest was carried out. Identification of the isolated alkaloid was performed by the use of thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) combined with electrospray ionization mass spectrometry (ESI-MS). The proposed approach was proved to be an efficient and accurate method for specific compound isolation and identification purposes. Moreover, analytical information from the CE approach can be considered as the valuable tool for binding constant determination. The binding constant of mitraphylline with Abeta1-40 protein determined by the Hummel-Dreyer method and Scatchard analysis equals K = 9.95 x 10(5) M(-1). The results obtained showed the significant binding of the tested compound with Abeta1-40 protein. These results are discussed and interpreted in the view of developing a strategy for identification of novel compounds of great importance in Alzheimer disease therapy.