Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors.

Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.     

Biodegradation of monoaromatic hydrocarbons by aquifer microorganisms using oxygen, nitrate, or nitrous oxide as the terminal electron acceptor.

Microcosms were prepared from aquifer material, spiked with monoaromatic hydrocarbons, and amended with oxygen, nitrate, and nitrous oxide. Benzene and alkylbenzenes were degraded to concentrations below 5 micrograms/liter within 7 days under aerobic conditions, whereas only the alkylbenzenes were degraded when either nitrate or nitrous oxide was used. With limited oxygen, monoaromatic hydrocarbons were degraded but removal ceased once oxygen was consumed. However, when nitrate was also present, biodegradation of the alkylbenzenes continued with no apparent lag. Although benzene was still recalcitrant, levels were reduced compared with levels after treatment with nitrate or limited oxygen alone.     

Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

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The conservation status of Texas groundwater invertebrates

Biodiversity conservation requires an objective and consistent method for evaluating the conservation status of species. Conservation status assessments can identify conservation priorities and can highlight data gaps, effective conservation strategies, and groups of taxa that are underrepresented in conservation efforts relative to charismatic flagship and umbrella species. Groundwater invertebrates have a suite of traits that make them inherently vulnerable. But they go largely unnoticed by the general public and conservation practitioners, and comprehensive conservation status assessments are lacking for most species. In this article, the conservation status of all sixty-nine described groundwater-obligate invertebrates recorded from Texas, U.S.A. was assessed using NatureServe methodology. Some of the smallest taxa (e.g. copepods, ostracods, and mites) are too poorly known to evaluate their conservation status. Species restricted to springs were generally more at risk than species in other groundwater habitats, and beetles and snails were the most imperiled taxonomic groups. Most species faced low or medium severity threats, and only seven percent faced high or very high magnitude threats. Threat level varied among aquifers and among sites within aquifers and was primarily dependent on human population density and the adequacy of regulatory mechanisms protecting groundwater quality and quantity. Regardless of threat severity, fifty-five percent of evaluated species were ranked as imperiled or critically imperiled, largely due to extreme small-range endemism. Relative to other regions, Texas’ groundwater fauna is not unique in terms of rarity and threat, suggesting that as an ecological group, groundwater-obligate species are probably among the world’s most imperiled taxa.     

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.     

Staining Scab Actinomyces in Potato Tuber Tissues

Actinomyces hyphae imbedded in the middle lamellae of potato tuber cells may be stained in sections by the use of a modified Gram's stain. The modifications are: a very strong (5%) solution of crystal violet in anilin oil; a 24-hour exposure to both the dye and the iodine solution; and a slow decolorization in absolute alcohol until no more color flows.     

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: Quinolin(di)one and benzazepin(di)one derivatives. herve.geneste@abbott.com

The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.     

Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme

In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.