Anilide tertiary carbinols: A new structural class of potent potassium channel openers

A new structural class of anilide tertiary carbinol potassium channel openers (PCOs) is described.     

Development of a new benzodiazepine hypnotics withdrawal symptom scale

Sleep and Biological Rhythms - For prevention and early detection of dependence on hypnotics such as benzodiazepines (BZDs) or its agonists, a withdrawal symptom scale specialized for this kind of...     

TULA‐family proteins: A new class of cellular regulators

Proteins of the UBASH3/STS/TULA family recently emerged as potent regulators of cellular functions. They are characterized by a unique architecture, featuring at least three functional domains. One of them is a histidine phosphatase domain, which mediates the protein tyrosine phosphatase activity of these proteins. Recent studies demonstrated that UBASH3/STS/TULA‐family proteins play a key role in down‐regulating receptor‐mediated signal transduction and physiologic responses of T cells and platelets in vitro and in vivo. The Syk‐family protein tyrosine kinases Syk and Zap‐70 were identified as major targets of TULA‐2 in full agreement with the suppressive effect of this phosphatase in systems where Syk and Zap‐70 carry out the essential early steps of signal transduction. In spite of significant similarity between TULA and TULA‐2, there are also considerable functional differences between them. Thus, TULA‐2 is expressed ubiquitously in mammalian tissues and exhibits high phosphatase activity, whereas TULA is expressed specifically in lymphocytes and exhibits low phosphatase activity. However, TULA also functions as a down‐regulator of cellular responses, and therefore its role may be mediated by dephosphorylation of yet‐unknown substrates or by promoting T‐cell apoptosis (the latter activity is unique for this UBASH3/STS/TULA family member). The down‐regulatory role of TULA and TULA‐2 revealed in experimental systems is consistent with the recently discovered association of several autoimmune diseases with certain risk alleles encoding for these proteins. J. Cell. Physiol. 228: 43–49, 2013. © 2012 Wiley Periodicals, Inc.     

A new class of antiarrhythmic-defibrillatory agents.

Novel dibenzoazepine and 11-oxo-dibenzodiazepine derivatives are shown to be effective ventricular defibrillating drug candidates. They exhibit significant in vivo defibrillatory activity with no observed changes in ECG either before or after the VF event. These compounds also exhibit antifibrillatory activity by elevating the fibrillation threshold potential, all suggesting that such drugs could be used to treat VF either by themselves or together with electrical defibrillators.     

A new class of membrane-associated calcium-binding proteins

Calcium ions act as modulators of many fundamental processes in eukaryotic cells. Although these processes apparently involve initial interactions between calcium ions and cell membranes, the identity of the putative membrane Ca²⁺-binding proteins has until recently been obscure. This article describes a recently discovered family of mammalian membrane proteins, of perhaps ancient origin, that may fulfil this function.     

A new class of potent gastrin antagonists

The hexapeptide Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, from the natural sequence of C-terminal cholecystokinin was found to be a competitive antagonist of cholecystokinin receptors, in vitro. In the present study, we report that this peptide inhibits gastrin-induced acid secretion in vivo, (ED50 = 1.5 mumol . kg-1), without agonist activity. Desulfation of the tyrosine residue slightly altered this effect. The tripeptide Boc-Trp-Met-Asp-NH2 showed similar effects, but had lower potency (ED50 = 12 mumol . kg-1). From these preliminary results, it can be concluded that removal of the phenylalanine residue from the C-terminal sequence of CCK or gastrin, leads to an antagonist of the natural hormones and that C-terminal phenylalanine residue is important for agonist activity. As compared with proglumide, a well known gastrin receptor antagonist, these peptides were 20-200 times more potent as inhibitors on the same model.     

A new class of glycogen phosphorylase inhibitors

A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.     

Isothiocyanates. A new class of uncouplers

This paper describes the uncoupling effect of three isothiocyanates: p-bromophenylisothiocyanate, 4,4′-diisothiocyanatebiphenyl and β-naphtylmethylisothiocyanate on the respiration of Ehrlich-Lettré cells and isolated mitochondria. The isothiocyanates are similar to other uncouplers (such as 2,4-dinitrophenol and carbonyl cyanide p-trifluoromethoxyphenylhydrazone) in that they: 1. stimulate respiration of state 4 mitochondria; 2. stimulate mitochondrial ATPase activity; 3. release the inhibition of mitochondrial respiration by oligomycin and 4. inhibit both mitochondrial respiration and mitochondrial ATPase activity at higher molar concentrations. The uncoupling activity of these isothiocyanates correlates well with their biological activity. Maximal activation of a latent mitochondrial ATPase activity of rat liver mitochondria in the presence of p-bromophenylisothiocyanate was found at a concentration of 15 μM. The investigated isothiocyanates differ significantly in their solubility in organic solvents and their chemical reactivity. We assume that the greater the partition coefficient in a series of isothiocyanates grouped according to the increasing value of log P (partition coefficient for the system octanol/water, 25 °C), the greater will be their uncoupling activity, but only up to a certain degree. Any further increase of log P will be marked by a decrease of this activity.     

A new class of tetraspanins in fungi

Tetraspanins are animal proteins involved in membrane complexes that are involved in cell adhesion, differentiation, and motility. The PLS1 gene from rice blast fungus Magnaporthe grisea encodes a protein (Pls1p) structurally related to tetraspanins that is required for pathogenicity. In Botrytis cinerea public sequences, we identified an EST homologous to PLS1. Using degenerated oligonucleotides, we amplified sequences homologous to PLS1 in fungi Colletotrichum lindemuthianum and Neurospora crassa. Analysis of N. crassa and M. grisea genome sequences revealed the presence of a single tetraspanin gene. Thus, fungi differ from animals, which contain between 20 and 37 paralogous tetraspanin genes. Fungal proteins encoded by BcPLS1, ClPLS1, and NcPLS1 display all the structural hallmarks of tetraspanins (predicted topology with four transmembrane domains, extra- and intracellular loops; conserved cysteine-based patterns in second extracellular loop). Phylogenetic analysis suggests that these genes define a new family of orthologous genes encoding fungal-specific tetraspanins.     

A new class of highly cytotoxic diketopiperazines

The discovery of a novel class of diketopiperazines possessing potent cytotoxic activity is described.     

A new class of cardiotonic steroids]

A series of 23-oxosteroid derivatives have been synthesized and tested for their inhibiting Na+, K(+)-dependent ATPase from rat brain in the 1 x 10(-6)-1 x 10(-4) M concentrations. Natural 23-oxogenins from sea star Asterias amurensis and synthetic monoesters showed the inhibiting activity upto 50-55%. These compounds caused heart contraction in frogs at the level of the known cardiotonic strophanthin G, and inotropic activity on isolated heart of mollusk Spisula sachalinensis.     

Possibilities and problems with identification and determination of "new" hypnotics

Authors discuss problems with identification and determination of flunitrazepam and zolpidem in biological material (BM). Over the recent years, these two structurally different substances have become the most frequently used as well as abused hypnotic drugs. This study presents applicability of immunochemical methods in the screening of flunitrazepam, one of the most commonly prescribed drugs among the benzodiazepines. Herein described techniques, a liquid-liquid (L-L) extraction, solid phase extraction (SPE) and the so-called "freeze out" method are used for isolation of the above mentioned compounds from BM. Besides the thin layer chromatography (TLC) and gas chromatography - mass spectrometry (GC-MS) applied in qualitative analysis, the study also describes a gas chromatography with electron capture detector (GC-ECD) and gas chromatography with nitrogen phosphorus detector (GC-NPD) optimized for the determination of flunitrazepam and zolpidem in blood (serum). Successful analyses of these two substances are of major importance, especially in interpreting the results of forensic toxicological examinations.     

A new class of network-polymeric chiral stationary phases

A strategy based on the use of homo bi- and multifunctional building blocks for the synthesis of a new class of network-polymeric chiral stationary phases has been evaluated. The key steps comprise acylation of N,N′-diallyl-L-tartardiamide (DATD) and reaction with a multifunctional hydrosilane, yielding a network polymer incorporating the bifunctional C₂-symmetric chiral selector. Covalent bonding to a functionalized silica takes place during the latter process. Many of these chiral sorbents show interesting enantioselective properties toward a wide variety of racemic solutes under normal-phase (hexane-based) conditions. The retention is mainly caused by the hydrogen-bonding ability of the analyte, which is regulated by mobile phase additives like alcohol or ether cosolvents. The most interesting chiral stationary phases, in terms of broad enantioselectivity, were obtained from O,O′-diaryol-DATD-derivatives, particularly those containing the 3,5-dimethylbenzoyl and the 4-(tert-butyl)benzoyl moieties. Since high column efficiencies can be obtained with these chiral sorbents, an α-value of ca. 1.2 is usually sufficient to produce baseline separation. A large number of neutral as well as acidic or basic drug racemates are resolved without derivatization. © 1995 Wiley-Liss, Inc.     

A new class of synthetic auxin transport inhibitors

Auxin transport inhibition by a new class of synthetic plant growth regulants, the 2-(3-aryl-5-pyrazolyl)benzoic acids, was examined in bean (Phaseolus vulgaris L.) using the donor-receiver agar cylinder technique. These compounds can be prepared by the dehydrogenation and ring cleavage of compounds like DPX-1840 (2-(4-methoxyphenyl)-3,3adihydro-8H-pyrazolo[5,1-a] isoindol-8-one) which was previously reported (Plant Physiol. 1972. 50: 322-327) to be a potent inhibitor of auxin transport. These new growth regulators inhibit auxin transport more than DPX-1840 does as evidenced by their consistently greater reduction of basipetal auxin transport capacity in bean when incorporated into the receiver agar cylinder or applied foliarly to intact plants. Direct comparisons of the effect of DPX-1840, its dehydrogenation product (2-(4-methoxyphenyl)-8H-pyrazolo [5,1-a]isoindol-8-one), and its open-ring form (2-(3-(4-methoxyphenyl)-5-pyrazolyl) benzoic acid) on auxin transport indicated the following order of activity: ring-open > dehydrogenated form > DPX-1840. DPX-1840-(14)C, applied at 0.5 mg/l to etiolated bean hypocotyl hooks followed by extraction and thin layer chromatography, indicated the biological conversion of DPX-1840 to its open-ring form. Collectively, these results suggest that the biologically active forms of DPX-1840-type compounds are the open-ring (2-(3-aryl-5-pyrazolyl) benzoic acids.     

Isothiocyanates. A new class of uncouplers.

This paper describes the uncoupling effect of three isothiocyanates: p-bromophenylisothiocyanate, 4,4'-diisothiocyanatebiphenyl and beta-naphtylemthylisothiocyanate on the respiration of Ehrlich-Lettré cells and isolated mitochondria. The isothiocyanates are similar to other uncouplers (such as 2,4-dinitrophenol and carbonyl cyanide p-trifluoromethoxyphenylhydrazone) in that they: 1. stimulate respiration of state 4 mitochondria; 2. stimulate mitochondrial ATPase activity; 3. release the inhibition of mitochondrial respiration by oligomycin and 4. inhibit both mitochondrial respiration and mitochondrial ATPase activity at higher molar concentrations. The incoupling activity of these isothiocyanates correlates well with their biological activity. Maximal activation of a latent mitochondrial ATPase activity of rat liver mitochondria in the presence of p-bromophenylisothiocyanate was found at a concentration of 15 muM. The investigated isothiocyanates differ significantly in their solubility in organic solvents and their chemical reactivity. We assume that the greater the partition coefficient in a series of isothiocyanates grouped according to the increasing value of log P (partition coefficient for the system octanol/water, 25 degrees C), the greater will be their uncoupling activity, but only up to a certain degree. Any further increase of log P will be marked by a decrease of this activity.