Synthesis and evaluation of heterocyclic carboxamides as potential antipsychotic agents.

Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl) benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-, 2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarboxamides). Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2 -pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) -2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.

Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates.

[formula: see text] The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps involved the enantioselective transfer hydrogenation of imine 8 employing Noyori's catalyst, the stereoselective crystallization and methanolysis of trans-bataines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14. The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.

Whiting events: biogenic origin due to the photosynthetic activity of cyanobacterial picoplankton.

An annual whiting event occurs each year in late May to early June in Fayetteville Green Lake, New York. The initiation of this event correlates with exponential growth of the Synechococcus population within the lake. Synechococcus is the dominant (by approximately 4 orders of magnitude) autotrophic organism owing to the oligotrophic condition of the lake. The delta 13C values of the dissolved inorganic C range seasonally from -9.5% in winter to -6.2% in summer due to photosynthetic activity. Calcite precipitates principally in the microenvironment surrounding Synechococcus because of a photosynthetically driven alkalization process and the availability of the cells as nucleation sites. This calcite has a heavier delta 13C value (>4%) than does the dissolved inorganic C of the lake water owing to the cells' preferential uptake of 12C. A conceptual model suggests that photosynthetic activity and cell surface chemistry, together with the substantial surface area that arises from the great abundance of micron-sized cells, allow Synechococcus to dominate the annual whiting events in Fayetteville Green Lake.

Relative importance of patient, procedural and anatomic risk factors for early vein graft thrombosis after coronary artery bypass graft surgery.

AIM: The aim of the present study was to investigate the relative importance of a wide array of patient demographic, procedural, anatomic and perioperative variables as potential risk factors for early saphenous vein graft (SVG) thrombosis after coronary artery bypass graft (CABG) surgery. METHODS: The patency of 611 SVGs in 291 patients operated on at four different hospitals enrolled in the Reduction in Graft Occlusion Rates (RIGOR) study was assessed six months after CABG surgery by multidetector computed tomography coronary angiography or clinically-indicated coronary angiography. The odds of graft occlusion versus patency were analyzed using multilevel multivariate logistic regression with clustering on patient. RESULTS: SVG failure within six months of CABG surgery was predominantly an all-or-none phenomenon with 126 (20.1%) SVGs totally occluded, 485 (77.3%) widely patent and only 16 (2.5%) containing high-grade stenoses. Target vessel diameter ≤ 1.5 mm (adjusted OR 2.37, P=0.003) and female gender (adjusted OR 2.46, P=0.01) were strongly associated with early SVG occlusion. In a subgroup analysis of 354 SVGs in which intraoperative graft blood flow was measured, lower mean flow was also significantly associated with SVG occlusion when analyzed as a continuous variable (adjusted OR 0.984, P=0.006) though not when analyzed dichotomously, <40 mL/min versus ≥ 40 mL/min (adjusted OR 1.86, P=0.08). CONCLUSION: Small target vessel diameter, female gender and low mean graft blood flow are significant risk factors for SVG thrombosis within six months of CABG surgery in patients on postoperative aspirin therapy. This information may be useful in guiding revascularization strategies in selected patients.

Plant antitumor agents. XVI. 6alpha-Senecioyloxy-chaparrinone, a new antileukemic quassinoid from Simaba multiflora.

Fractionation of Simaba multiflora A. Juss. guided by bioassay has resulted in the isolation of a new antileukemic quassinoid 6alpha-senecioyloxychaparrinone (2) and the previously reported quassinoid chaparrinone (3). The structure of the former has been established by spectral and chemical methods. Compound 2 has high anti-neoplastic activity against several mouse leukemia systems (P-388, L-1210 and in solid-tumor B-16 melanoma). This demonstrates for the first time that the presence of a C-15 ester function is not required for antineoplastic activity in the quassinoids.

Prolonged corticotrophic action of a synthetic substituted 1-18 ACTH.

The adrenocorticotrophic effects of a synthetic corticotrophin analogue, alpha(1-18) ACTH with D-serine(1), lysine(17), and lysine amide(18) substitutions has been studied. It is effective after both intramuscular and subcutaneous administration and compared with tetracosactrin depot (Synacthen depot, Cortrosyn depot) it has a similarly prolonged time course of action-about 24 hours after 0.5 mg and 30 hours after 1 mg. Unlike tetracosactrin depot, however, it is well absorbed when given intranasally and does not produce painful reactions at the site of injection. Its prolonged time course of action does not depend on a formulation designed to delay its release from the injection site but most probably on a decreased rate of degradation in the circulation.

Effects of varying inspiratory flow waveform and time in intermittent positive pressure ventilation: pulmonary oedema.

Greyhound dogs were given oleic acid i.v. to induce controlled pulmonary oedema. These animals were then studied using intermittent positive pressure ventilation (IPPV) with four different inspiratory flow waveforms, each at three different inspiratory times, in a fixed respiratory cycle of 4 s at a constant tidal volume. Although there were statistically significant differences in airway and oesophageal pressures between the different waveforms and times, there was little variation in the other physiological parameters studied except for arterial carbon dioxide tension. (PaCO2) which showed statistically significant improvement with reversed ramp and sine wave inputs and at the longer inspiratory time of 2.2s. Venous admixture (Qs/Qt) was also less with the longer inspiratory time of 2.2s.

Segmented nanofibers of spider dragline silk: atomic force microscopy and single-molecule force spectroscopy.

Despite its remarkable materials properties, the structure of spider dragline silk has remained unsolved. Results from two probe microscopy techniques provide new insights into the structure of spider dragline silk. A soluble synthetic protein from dragline silk spontaneously forms nanofibers, as observed by atomic force microscopy. These nanofibers have a segmented substructure. The segment length and amino acid sequence are consistent with a slab-like shape for individual silk protein molecules. The height and width of nanofiber segments suggest a stacking pattern of slab-like molecules in each nanofiber segment. This stacking pattern produces nano-crystals in an amorphous matrix, as observed previously by NMR and x-ray diffraction of spider dragline silk. The possible importance of nanofiber formation to native silk production is discussed. Force spectra for single molecules of the silk protein demonstrate that this protein unfolds through a number of rupture events, indicating a modular substructure within single silk protein molecules. A minimal unfolding module size is estimated to be around 14 nm, which corresponds to the extended length of a single repeated module, 38 amino acids long. The structure of this spider silk protein is distinctly different from the structures of other proteins that have been analyzed by single-molecule force spectroscopy, and the force spectra show correspondingly novel features.

Bone indentation recovery time correlates with bond reforming time.

Despite centuries of work, dating back to Galileo, the molecular basis of bone's toughness and strength remains largely a mystery. A great deal is known about bone microsctructure and the microcracks that are precursors to its fracture, but little is known about the basic mechanism for dissipating the energy of an impact to keep the bone from fracturing. Bone is a nanocomposite of hydroxyapatite crystals and an organic matrix. Because rigid crystals such as the hydroxyapatite crystals cannot dissipate much energy, the organic matrix, which is mainly collagen, must be involved. A reduction in the number of collagen cross links has been associated with reduced bone strength and collagen is molecularly elongated ('pulled') when bovine tendon is strained. Using an atomic force microscope, a molecular mechanistic origin for the remarkable toughness of another biocomposite material, abalone nacre, has been found. Here we report that bone, like abalone nacre, contains polymers with 'sacrificial bonds' that both protect the polymer backbone and dissipate energy. The time needed for these sacrificial bonds to reform after pulling correlates with the time needed for bone to recover its toughness as measured by atomic force microscope indentation testing. We suggest that the sacrificial bonds found within or between collagen molecules may be partially responsible for the toughness of bone.

Cotransfection of second and third intracellular loop fragments inhibit angiotensin AT1a receptor activation of phospholipase C in HEK-293 cells.

Peptides from the intracellular regions of G protein-coupled receptors are useful probes of receptor-G protein coupling mechanisms. As a first step toward the genetic delivery of such "G protein inhibitors," we describe inhibition of angiotensin II (AII) receptor responses by expressed fragments of the second and third intracellular loops of the AT1a receptor (AT1a/i2 and AT1a/i3). Transient transfection of human embryonic kidney 293 cells with DNA encoding the rat AT1a receptor resulted in AII-dependent increases of inositol phosphates (maximum 4.5-fold). Cotransfection of AT1a/i2 and AT1a/i3 fragments raised the EC50 for AII stimulation of phospholipase C activity 5-fold (from 0.18 nM to 0.99 nM, n = 12, P < .001) and 3-fold (from 0.38 nM to 1.2 nM, n = 8, P < .002), respectively. The combined effect of AT1a/i2 and AT1a/3 was additive, and transfection of an alpha-1b adrenergic receptor third intracellular loop (alpha1b/i3) fragments also increased the EC50 for AII. Neither AT1a/i1 nor C-terminus (AT1a/Ct) constructs had significant effects on angiotensin responses. These data confirm a role for the second and third intracellular loops in angiotensin receptor responses and show the potential of this approach to blocking multiple phospholipase C-linked receptors.

Plant antitumor agents, 19. Novel triterpenes from Maprounea africana.

Four new pentacyclic triterpenes have been isolated from Maprounea africana. These triterpenes are members of the previously unknown urs-12-en-29-oic acid series. The structures of these compounds were deduced from spectral and chemical evidence. The parent compound, maprounic acid, was identified as 3B-hydroxyurs-12-en-29-oic acid. The remaining three triterpenes were identified as maprounic acid 3-p-hydroxybenzoate, 7 beta-hydroxymaprounic acid 3-p-hydroxybenzoate, and 2 alpha-hydroxymaprounic acid 2,3-bis-p-hydroxybenzoate. Of the four triterpenes, only the 7 beta-hydroxy derivative exhibited in vivo P-388 activity.