Bond Behavior of FRP Bars in Lightweight SCC under Direct Pull-Out Conditions: Experimental and Numerical Investigation.

In recent decades, lightweight aggregate concrete (LWC) became a popular building material due to its desired properties. However, various attributes of LWC, such as bond behavior of used reinforcing, have not been described thoroughly. In this regard, LWC produced with 0%, 50%, and 100% expanded clay aggregate was designed, and the physical-mechanical properties were assessed for material characterization. Subsequently, the bond behaviors of LWC reinforced with steel, glass fiber reinforced polymer (GFRP), and basalt fiber reinforced polymer (BFRP) bars were evaluated by pull-out tests. The results of the experimental program allowed the effects of expanded clay aggregate incorporation on LWC properties to be quantified. The bond strength of BFRP bars was not affected by the replacement of coarse aggregate by expanded clay aggregate, whilst the GFRP bars showed lower bond strength values of LWC specimens. Contrarily, in the case of steel bars, both the bond strength and bond stiffness were higher for LWC specimens than for those of normal concrete. Finite element software ATENA 3D was used for simulation of the bond behavior of LWC, and the model validated by the experimental results referred to reasonably corresponding outputs.

Potent analogues of etiprednol dicloacetate, a second generation of soft corticosteroids.

OBJECTIVES: Loteprednol etabonate (LE) is the first, highly successful soft corticosteroid (SC) designed using the 'inactive metabolite' approach, starting with ∆1 -cortienic acid (d-CA). The next generation of SCs based on d-CA was etiprednol dicloacetate (ED). The 17α-dichloroacetyl function serves both as a unique pharmacophore and as the source of the molecule's softness. Highly potent SCs were designed based on a combination of ED and LE, introducing 6, 9 and 16 substituents in the molecule. METHODS: The new 6α, 9α, 16α and ß 17α-dichloroacetyl 17ß-esters were synthesized from the correspondingly substituted ∆1 -cortienic acids. The anti-inflammatory activity was assessed using LPS-induced TNF α-release under various conditions to determine intrinsic activity vs. systemic biological stability. In vivo anti-inflammatory activity was studied in the widely used ovalbumin-sensitized and ovalbumin-challenged Brown Norway rat model. KEY FINDINGS: The 6α or 9α-fluoro substitution produced highly potent corticosteroids, but the 17α-dichloroacetyl substituent provided 'softness' in all cases. Local application of these steroids will significantly reduce systemic activity, due to the facile hydrolytic deactivation of these molecules. CONCLUSIONS: A 17α-dichloroacetyl derivative of fluticasone (FLU) is highly potent but much safer than the currently used propionate or furoate ester.

New features in synthesis of talampanel related 2,3-benzodiazepines.

Analogues of talampanel (1), a highly active AMPA antagonist 2,3-benzodiazepine, were synthesized, where the characteristic amino-function was either transposed or sterically shielded. For the key intermediates (hemiketals 6a, b) a new synthetic method of different mechanism was developed. The inactivity of several new compounds indicates the significance of the 4-amino(phenyl) function in BDZs of type 1.

Non-competitive AMPA antagonists of 2,3-benzodiazepine type.

The discovery of the selective AMPA antagonist character of 2,3-benzodiazepine derivative GYKI 52466 (5) in the late eighties and the recognition of the non-competitive nature of its mode of action some years later set off the world-wide search for novel class of drugs. Notably the quest to develop new antiepileptic and neuroprotective medicines, which allosterically inhibit the AMPA sensitive glutamate operated channels. This review summarises our present knowledge about the allosteric site, dubbed "GYKI site" where the 2,3-benzodiazepines are supposed to bind to. The structure-activity relationships among AMPA antagonist 2,3-benzodiazepines and their structural analogues with similar biological profile are reviewed in a possibly comprehensive fashion. The chemical synthesis of 2,3-benzodiazepines is shortly described. The in vitro and in vivo experimental methods used for pharmacological characterisation of the biologically active compounds are briefly explained. Finally the therapeutic potential of 2,3-benzodiazepines i.e. the main fields of their clinical utility are outlined with special regard to talampanel (20) in the light of the ongoing clinical trials with this new drug candidate.

Mechanism and site of inhibition of AMPA receptors: pairing a thiadiazole with a 2,3-benzodiazepine scaffold.

2,3-Benzodiazepine compounds are synthesized as drug candidates for treatment of various neurological disorders involving excessive activity of AMPA receptors. Here we report that pairing a thiadiazole moiety with a 2,3-benzodiazepine scaffold via the N-3 position yields an inhibitor type with >28-fold better potency and selectivity on AMPA receptors than the 2,3-benzodiazepine scaffold alone. Using whole-cell recording, we characterized two thiadiazolyl compounds, that is, one contains a 1,3,4-thiadiazole moiety and the other contains a 1,2,4-thiadiazole-3-one moiety. These compounds exhibit potent, equal inhibition of both the closed-channel and the open-channel conformations of all four homomeric AMPA receptor channels and two GluA2R-containing complex AMPA receptor channels. Furthermore, these compounds bind to the same receptor site as GYKI 52466 does, a site we previously termed as the "M" site. A thiadiazole moiety is thought to occupy more fully the side pocket of the receptor site or the "M" site, thereby generating a stronger, multivalent interaction between the inhibitor and the receptor binding site. We suggest that, as a heterocycle, a thiadiazole can be further modified chemically to produce a new class of even more potent, noncompetitive inhibitors of AMPA receptors.

Potential metabolites of a condensed 2,3-benzodiazepine derivative.

Putative metabolites of an AMPA antagonist imidazo-2,3-benzodiazepine (2) were synthesized and compared to constituents formed from the parent compound by a rat liver perfusion method. As metabolic transformations, hydroxylation of the 2-methyl group and N-acetylation of the amino functionality in parent compound (2) were registered. The hydroxylated analogue 12 of 2 exhibits a weak AMPA antagonist activity.