2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors

2-Amino-3-benzoylthiophenes are allosteric enhancers (AE) of agonist activity at the A₁ adenosine receptor. The present report describes syntheses and assays of the AE activity at the human A₁AR (hA₁AR) of a panel of compounds consisting of nine 2-amino-3-aroylthiophenes (3a-i), eight 2-amino-3-benzoyl-4,5-dimethylthiophenes (12a-h), three 3-aroyl-2-carboxy-4,5- dimethylthiophenes (15a-c), 10 2-amino-3-benzoyl-5,6-dihydro 4H-cyclopenta[b]thiophenes (17a-j), 14 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophenes (18a-n), and 15 2-amino- 3-benzoyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenes (19a-o). An in vitro assay employing the A₁AR agonist [¹²⁵I]ABA and membranes from CHO-K1 cells stably expressing the hA¹AR measured, as an index of AE activity, the ability of a candidate AE to stabilize the agonist- A₁AR-G protein ternary complex. Compounds 3a-i had little or no AE activity, and compounds 12a-h had only modest activity, evidence that AE activity depended absolutely on the presence of at least a methyl group at C-4 and C-5. Compounds 17a-c lacked AE activity, suggesting the 2-amino group is essential. Polymethylene bridges linked thiophene C-4 and C-5 of compounds 17a-j, 18a-n, and 19a-o. AE activity increased with the size of the -(CH₂)_n- bridge, n ) 3 < n ) 4 < n ) 5. The 3-carbethoxy substituents of 17a, 18a, and 19a did not support AE activity, but a 3-aroyl group did. Bulky (or hydrophobic) substituents at the meta and para positions of the 3-benzoyl group and also 3-naphthoyl groups greatly enhanced activity. Thus, the hA₁AR contains an allosteric binding site able to accommodate 3-aroyl substituents that are bulky and/or hydrophobic but not necessarily planar. A second region in the allosteric binding site interacts constructively with alkyl substituents at thiophene C-4 and/or C-5.

Crystal structure of (3S*,4S*)-4-hydroxy-2-(2`-methoxyethyl)-3-phenyl-3,4-dihydroisoquinol-1(2H)-one,C18H19NO3

C₁₈H₁₉N0₃, monoclinic, P12₁/n1 (No. 14), a =8.454(6) Å,
b =13.123(3) Å, c =14.698(3) Å, ß =104.85(3)^o, V =1576.2ų,
Z =4, R_gt(F) =0.062, wR_ref(F²) =0.184, T =293 K.

Weak intermolecular interactions in sulfonamide salts : structure of 1-ethyl-2-methyl-3-benzyl imidazolium bis[(trifluoromethyl)sulfonyl]amide

The crystal structure of a 1,2,3-trisubstituted imidazolium salt of the bis[(trifluoromethyl)sulfonyl)]amide ion is presented; this salt is a prototype for similar, room temperature liquid, imidazolium salts; the structure shows that the anion and cation interact weakly, with little if any hydrogen bonding present.

Outcomes of population based language promotion for slow to talk toddlers at ages 2 and 3 years: let’s learn language cluster randomised controlled trial

Objective To determine the benefits of a low intensity parent-toddler language promotion programme delivered to toddlers identified as slow to talk on screening in universal services.
Design Cluster randomised trial nested in a population based survey.
Setting Three local government areas in Melbourne, Australia.
Participants Parents attending 12 month well child checks over a six month period completed a baseline questionnaire. At 18 months, children at or below the 20th centile on an expressive vocabulary checklist entered the trial.
Intervention Maternal and child health centres (clusters) were randomly allocated to intervention (modified “You Make the Difference” programme over six weekly sessions) or control (“usual care”) arms.
Main outcome measures The primary outcome was expressive language (Preschool Language Scale-4) at 2 and 3 years; secondary outcomes were receptive language at 2 and 3 years, vocabulary checklist raw score at 2 and 3 years, Expressive Vocabulary Test at 3 years, and Child Behavior Checklist/1.5-5 raw score at 2 and 3 years.
Results 1217 parents completed the baseline survey; 1138 (93.5%) completed the 18 month checklist, when 301 (26.4%) children had vocabulary scores at or below the 20th centile and were randomised (158 intervention, 143 control). 115 (73%) intervention parents attended at least one session (mean 4.5 sessions), and most reported high satisfaction with the programme. Interim outcomes at age 2 years were similar in the two groups. Similarly, at age 3 years, adjusted mean differences (intervention−control) were −2.4 (95% confidence interval −6.2 to 1.4; P=0.21) for expressive language; −0.3 (−4.2 to 3.7; P=0.90) for receptive language; 4.1 (−2.3 to 10.6; P=0.21) for vocabulary checklist; −0.5 (−4.4 to 3.4; P=0.80) for Expressive Vocabulary Test; −0.1 (−1.6 to 1.4; P=0.86) for externalising behaviour problems; and −0.1 (−1.3 to 1.2; P=0. 92) for internalising behaviour problems.
Conclusion This community based programme targeting slow to talk toddlers was feasible and acceptable, but little evidence was found that it improved language or behaviour either immediately or at age 3 years.

2 or 3 things I remember or should have known about him

Optic Antics celebrates the work of Film Artist Ken Jacobs’ substantial and ongoing materialist practice, straddling more than 50 years, complicit in the 60s explosion of experimental film and now witnessing and commenting on the digital onslaught. This practice includes 16mm films that are recognized as foundation works for an experimental artist based cinema, celebrated and ongoing film performances and a renewed digital practice that re-animates historic 3-D images in flicker form.

ß1/ß2/ß3-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting

Catecholamines are viewed as major stimulants of diet- and cold-induced thermogenesis and of fasting-induced lipolysis, through the β-adrenoceptors (β1/β2/β3). To test this hypothesis, we generated β1/β2/β3-adrenoceptor triple knockout (TKO) mice and compared them to wild type animals. TKO mice exhibited normophagic obesity and cold-intolerance. Their brown fat had impaired morphology and lacked responses to cold of uncoupling protein-1 expression. In contrast, TKO mice had higher circulating levels of free fatty acids and glycerol at basal and fasted states, suggesting enhanced lipolysis. Hence, β-adrenergic signalling is essential for the resistance to obesity and cold, but not for the lipolytic response to fasting.

Chemisorbed and physisorbed Structures for 1,10-Phenanthroline and Dipyrido[3,2-a:2',3'-c]phenazine on Au(111)

Scanning tunneling microscopy (STM) images of 1,10-phenanthroline (PHEN) and dipyrido[3,2-a:2‘,3‘-c]phenazine (DPPZ) on Au(111) are recorded using both in situ and ex situ techniques. The images of PHEN depict regimes of physisorption and chemisorption, whereas DPPZ is only physisorbed. All physisorbed structures are not pitted and fluctuate dynamically, involving aligned (4 × 4) surface domains with short-range (ca. 20 molecules) order for PHEN but unaligned chains with medium-range (ca. 100 molecules) order for DPPZ. In contrast, the chemisorbed PHEN monolayers remain stable for days, are associated with surface pitting, and form a (4 × √13)R46° lattice with long-range order. The density of pitted atoms on large gold terraces is shown to match the density of chemisorbed molecules, suggesting that gold adatoms link PHEN to the surface. For PHEN, chemisorbed and physisorbed adsorbate structures are optimized using plane-wave density-functional theory (DFT) calculations for the surface structure. Realistic binding energies are then obtained adding dispersive corrections determined using complete-active-space self-consistent field calculations using second-order perturbation theory (CASPT2) applied to cluster-interaction models. A fine balance between the large adsorbate−adsorbate dispersive forces, adsorbate−surface dispersive forces, gold ligation energy, and surface mining energy is shown to dictate the observed phenomena, leading to high surface mobility and substrate/surface lattice incommensurability. Increasing the magnitude of the dispersive forces through use of DPPZ, rather than PHEN, to disturb this balance produced physisorbed monolayers without pits and/or surface registration but with much longer-range order. Analogies are drawn with similar but poorly understood processes involved in the binding of thiols to Au(111).

Design of 1,2-dioxines with anti-Candida activity: aromatic substituted 1,2-dioxines

In an ongoing effort to rationally design new antimicrobials, 47 new 1,2-dioxines have been synthesised. Broad antifungal structure-activity relationships governing aromatically substituted epoxy-1,2-dioxines 2 and 3 and their parent 1,2-dioxines 1 were assessed primarily against the pathogenic yeast, Candida albicans, with haemolytic activity of selected examples also reported.

Electrophilic substitution of acetyltrimethylsilane with tellurium(IV) halides: A synthetic route to 3-methyl-5-(trimethylsilyl)-1,2-oxatellurol-1-ium halides

The reaction of tellurium tetrahalides, TeX4 (XCl. Br) with acetyltrimethylsilane in CCl4 at ambient temperature, unlike that of the aryltellurium trichlorides, ArTeCl3 that give the expected electrophilic substitution products, Ar(Me3SiCOCH2)TeCl2, (Ar = 1-C10H7, 2; 2,4,6-Me3C6H2, 3), afforded novel silylated heterocycles, 3-methyl-5-(trimethylsilyl)-1,2-oxatellurol-1-ium halides 1a and 1b. These Te(II) heterocyclic compounds undergo halide exchange with sodium iodide and also add dihalogens oxidatively to afford the corresponding iodide, 1c and the Te(IV) trihalides, 5a and 5b respectively. A large lowering of ν(CO) is indicative of strong Te⋯OC interactions among these heterocycles, and is also substantiated by single-crystal X-ray diffraction data for 3-methyl-5-(trimethylsilyl)-1,2-oxatellurol-1-ium chloride. The ¹²⁵Te chemical shifts for the new 10-Te-3 telluranes and 12-Te-5 pertelluranes that involve tellurium bound to two highly electronegative atoms (O, X) are among the highest (downfield) reported for organotellurium(II) and (IV) compounds.