Surviving the Vajont disaster: psychiatric consequences 36 years later

The aim of the present study was to assess the chronic psychiatric consequences of the Vajont disaster in a group of survivors still living in the valley 36 years after the event. Thirty-nine subjects were assessed by means of a semistructured interview to investigate the extent of the traumatic experience and a structured diagnostic interview for the diagnoses of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The degree of traumatic exposure significantly predicts the presence of PTSD. The lifetime frequency of full PTSD was 26%, and a further 33% of the sample displayed partial PTSD. Lifetime MDD was present in 28% of the subjects, and its prediction factors were female gender and number of losses of first-degree relatives in the disaster. Trauma-related fears are very common in the sample. A large-scale disaster, such as that of the Vajont valley, affects the psychological health of survivors for decades

New azepino[4,3-b]indole derivatives, as selective butyrylcholinesterase inhibitors with potential for neurodegenerative disorders

Starting from the cholinergic hypothesis, which originally implied a major role of acetylcholinesterase (AChE) in the cognitive impairment of the Alzheimer’s disease (AD), the role of butyrylcholinesterase (BChE) has progressively become more crucial in the AD development and progression. Indeed, it has been shown that the levels of AChE in the AD brain decrease by as much as 90%, whilst the levels of BChE, mainly in the G1 form (i.e., globular form of monomer structure), increase, suggesting that inhibition of BChE may represent a privileged target to develop new drugs for treating neurodegenerative diseases. As a matter of fact, in the last years several efforts have been made to identify selective BChE inhibitors, such as tricyclic cymserine analogs, which proved beneficial in vivo in animal models, most likely by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Previously, we reported the ChE inhibition activity of novel medium-sized nitrogen-containing heterocycles (e.g., tetrahydroazocines) fused on indole, which showed ChE inhibition activity. Herein, we explore the ChE inhibition activity of a series of 3,4,5,6-tetrahydroazepino[4,3-b]indole derivatives, some of which proved to be highly potent and selective BChE inhibitors, with low toxicity as assessed in vitro on neuroblastoma cell cultures. Among the newly synthesized compounds, the lactam derivative 2 showed the highest BChE inhibition potency (IC50 = 1.5 nM), whereas further investigation showed that the above tricyclic system could provide a promising scaffold for new multimodal derivatives with potential in the treatment of neurodegenerative disorders

The exploration of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole derivatives as selective butyrylcholinesterase inhibitors

The role of butyrylcholinesterase (BChE) in the progression of Alzheimer’s disease (AD) has recently become more crucial (1). It is known that in healthy human brain acetylcholinesterase (AChE) predominates over BChE activity, but, as AD progresses, The levels of AChE in the brain decrease by as much as 90%, whilst the levels of BChE, Mainly in the G1 form (i.e., globular form of monomer structure), increase (2,3). This suggests that the inhibition of BChE may be useful in ameliorating the cholinergic transmission, which likely worsen in AD due to the BChE increased activity (4). As a matter of fact, in the AD brain, selective BChE inhibitors, such as tricyclic cymserine Analogs (1,5), have been demonstrated to have beneficial effects in vivo, probably by recovering cholinergic activity and/or by restoring AChE:BChE activity ratios to the levels observed in the healthy brain. Some years ago, we reported the ChE inhibition activity of novel annulated (e.g., pyrrole- and indole-fused) tetrahydroazocines, which showed AChE selectivity (6). Herein, we explore the ChE inhibition activity of a large series of 1,2,3,4,5,6-hexahydroazepino[4,3-b]ndole derivatives, some of which proved to be potent and selective BChE inhibitors. In particular, the lactam derivative 2 was highly active against BChE, with a subnanomolar IC50 Value. Synthesis, enzyme inhibition data and SARs are presented and discussed

Fragment deconstruction study and human thrombin-bound crystal structures of new β-d-glucose-containing anticoagulants

We recently synthesized novel glucose-conjugated dual factor Xa (fXa) and thrombin (fIIa) inhibitors 3, bearing 5-chlorothien-2-yl and 1-isopropylpiperidine moieties as binders of the S1 and S3/S4 enzymes’ pockets, respectively, which showed potential for use in the treatment of thrombotic diseases. In particular, the β-d-glucosyl-bearing derivative proved to be a competitive inhibitor with high potency against fXa (Ki = 0.09 nM) and fIIa (Ki = 100 nM), and in vitro/ex vivo micromolar anticoagulant potency.1 Despite the narrower binding site groove of fIIa, the inhibitory potency of the glucosyl derivative, compared to the parent glucosyl-lacking compound 1, increases against fIIa (110-fold) much more than against fXa (7-fold). Experimental deconstruction of the most potent inhibitor molecule into smaller fragments, synthesized and tested, provided us with significant insights into the enzymes’ affinity contributions of the P1 and P3/P4 moieties, and a C3-alkyl-linked -d-glucose fragment (PG). To understand the inhibitors’ binding modes to fIIa, the crystal structures of human thrombin in complex with two glucose-based compounds were solved (pdb codes: 4NZE and 4N3L), and the crystallographic results will be presented and discussed