Pyrrole-Based Zwitterionic π-Electronic Systems That Form Self-Assembled Dimers.

Pyrrole-based zwitterionic π-electronic systems including a phenylcarboxylate (benzoate) anionic site and an N-methyl pyridinium cation unit were synthesized. Spectroscopic and theoretical examinations revealed the intermolecular hydrogen-bonding interactions of the pyrrole NH group and the 3-pyridinium and 3-benzoate ortho-CH moieties of zwitterions with a carboxylate anion to form self-assembled dimers. The self-assembled dimers were found to exist in equilibrium with the corresponding monomers in DMSO, whose dimerization ability was examined by concentration-dependent measurements.

Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain.

The purpose of this study was to develop three new radiotracers, 1-(cyclopropylmethyl)-4-([11C/18F]substituted-phenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([11C]1, [11C]2, and [18F]4), and to examine their specific bindings with metabotropic glutamate receptor subtype 2 (mGluR2) in rat brain sections by using in vitro autoradiography. These compounds were found to possess potent in vitro binding affinities (Ki: 8.0-34.1nM) for mGluR2 in rat brain homogenate. [11C]1, [11C]2, and [18F]4 were synthesized by [11C/18F]alkylation of the corresponding phenol precursors with [11C]methyl iodide or [18F]fluoroethyl bromide with >98% radiochemical purity and 80-130GBq/µmol specific activity at the end of synthesis. In vitro autoradiography indicated that these radiotracers showed heterogeneous specific bindings in mGluR2-rich brain regions, such as the cerebral cortex, striatum, hippocampus, and granular layer of the cerebellum.

Acute Renal Injury Induced by Hypersensitivity to Tolvaptan in an Elderly Patient with Congestive Heart Failure.

Tolvaptan (TLV) is a new vasopressin type 2 receptor antagonist effective in patients with heart failure (HF). We herein describe the case of an 84-year-old woman who developed acute renal injury induced by hypersensitivity to TLV. The patient had received an implanted pacemaker and was diagnosed with exacerbation of chronic HF due to atrial fibrillation, mitral regurgitation, tricuspid regurgitation and left ventricular dyssynchrony. Treatment with tolvaptan increased the urine volume, improved the dyspnea and decreased the edema. However, the patient's renal function and hyperkalemia worsened, and the blood eosinophil count increased without signs of dehydration or hypotension. Positive findings on a drug-induced lymphocyte stimulation test for TLV were consistent with this diagnosis.

Transcriptional regulation of the rainbow trout CYP19a gene by FTZ-F1 homologue.

In rainbow trout, there are at least two CYP19 genes (CYP19a and CYP19b). They encode distinct P450arom isozymes that are differentially expressed in the ovary and brain. To understand the transcriptional regulation of the rainbow trout CYP19a (rtCYP19a) gene in the ovary, we isolated its 5'-flanking region. The presence of potential FTZ-F1-binding sites prompted us to isolate the cDNA encoding a rainbow trout FTZ-F1 homologue (rtFTZ-F1) and analyze its effect on the rtCYP19a gene transcriptional activity. RT-PCR analysis showed overlapping expression of the rtCYP19a and rtFTZ-F1 genes in the ovary. Transient transfection studies in Chinese hamster ovary-derived CHO-K1 cells revealed that the region from -247 to -105, which contains three potential FTZ-F1-binding sites, was required for rtFTZ-F1-mediated transcriptional activation of the rtCYP19a gene. Among the three potential binding sites, the two from -150 to -142 and from -118 to -110 showed strong affinities for rtFTZ-F1 in gel shift assays, and base substitutions in either site almost abolished the transcriptional activation by rtFTZ-F1. Taken together, these results demonstrate that rtFTZ-F1 plays an important role in the transcriptional regulation of the rtCYP19a gene in the ovary.

Adenovirus vector-mediated reporter system for in vivo analyses of human CYP3A4 gene activation.

The use of cultured mammalian cells and artificial promoters for analyses of gene regulation gives results that are sometimes inconsistent with in vivo events and thus inconclusive. To understand the in vivo mechanism of chemically mediated CYP3A4 gene activation, we have used a natural promoter of the CYP3A4 gene and an adenovirus as a reporter vector. The adenovirus reporter vector (AdCYP3A4-362) was constructed with a proximal promoter region (-362 to +11 nt) of the CYP3A4 gene and a luciferase-reporter gene. AdCYP3A4-362 was then infected into mice, and both the reporter and mouse CYP3A activities were measured. Clear increases in the reporter activity were observed in livers of all mice treated with chemicals. The profile of the CYP3A4 gene activation with chemicals was in good agreement with that of endogenous mouse CYP3A-mediated testosterone 6beta-hydroxylase. Introduction of nucleotide mutations in the receptor-binding region (ER-6) of the CYP3A4 promoter resulted in diminished reporter activity. These results indicate the advantage of the adenovirus-mediated in vivo system over the currently available in vitro systems for gene transcriptional activation.