Azulene-based compounds for targeting orexin receptors

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved.Peer reviewe

The azulene scaffold from a medicinal chemist's perspective : Physicochemical and in vitro parameters relevant for drug discovery

Azulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We syn-thesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution patterns. Generally, we conclude that azulene is an underused lipophilic bicycle and should be considered as a valuable complement to the collection of medicinal chemistry scaffolds. (c) 2022 The Authors. Published by Elsevier Masson SAS.Peer reviewe

Some small-emittance light-source lattices with multi-bend achromats

Two examples of low-emittance light-source lattices are discussed. Both use similar building blocks consisting of 7-bend achromats. The small emittances generated by these lattices are further reduced by the introduction of insertion devices (IDs), resulting in beam emittance values ranging from 0.2 to 0.9 nm rad, depending on the number of achromats chosen. The two examples discussed here are rings with 12 and 20 achromats. The performances of any intermediate number of achromats can easily be estimated. A higher number of achromats of this type seems to result in an uncomfortably small dynamic aperture. The Touschek losses and Intra Beam Scattering (IBS) effect are calculated together with some means to reduce their impact. To calculate this impact, certain technical solutions are assumed, which are described. Other technical solutions could naturally be chosen. The impact of emittance on brilliance is also discussed and the brilliance curves for the two cases are presented and compared with the zero-emittance case ("ultimate source"). (C) 2008 Elsevier B.V. All rights reserved

Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists

Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 +/- 0.07, maximum response = 81 +/- 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site.Peer reviewe

Use of heated tobacco products (IQOS) causes an acute increase in arterial stiffness and platelet thrombus formation

Background and aims: Heated tobacco products (HTPs) are novel alternative tobacco products being promoted as an alternative to cigarettes. To evaluate the impact of HTP use on vascular function, we investigated the effects of a brief HTP usage on arterial stiffness and platelet thrombus formation in healthy volunteers. Methods: In a randomised crossover study, twenty-four healthy young adults with occasional tobacco use smoked the HTP IQOS 3 Multi (Phillip Morris Int.) and “no-exposure” was used as a control, with a wash-out period of at least one week in-between. Arterial stiffness was assessed through pulse wave velocity and pulse wave analysis. Blood samples, collected at baseline and 5 min following exposure, were analysed with the Total-Thrombus-formation analysis system evaluating platelet and fibrin-rich thrombus formation tendency. Results: HTP exposure caused immediate heightened pulse wave velocity (+0.365 m/s, 95% CI: +0.188 to 0.543; p = 0.004) and enhanced augmentation index corrected to heart rate (+6.22%, 95% CI: +2.33 to 10.11; p = 0.003) compared to the no-exposure occasion. Similarly, blood pressure and heart rate transiently increased immediately following HTP inhalation. Platelet thrombus formation significantly increased following HTP exposure (area under the curve +59.5, 95% CI: +25.6 to 93.4; p < 0.001) compared to no-exposure. No effect was seen on fibrin-rich thrombus formation following HTP-exposure. Conclusions: Brief HTP use in healthy young adults had immediate adverse effects on vascular function resulting in increased arterial stiffness and platelet thrombus formation, known risk factors for the development of atherosclerosis. Further research is needed to address long term health impacts

Electronic cigarette vaping with nicotine causes increased thrombogenicity and impaired microvascular function in healthy volunteers : a randomised clinical trial

Electronic cigarette (EC) vaping is increasingly popular, despite growing evidence of adverse health effects. To further evaluate the impact of EC use on vascular health, we investigated the effects of brief EC inhalation on flow-dependent thrombus formation and microcirculation in healthy volunteers. The study was performed with a randomised double-blind crossover design. Twenty-two healthy subjects aged between 18 and 45 years with occasional tobacco use were recruited. Subjects inhaled 30 puffs of EC aerosol with and without nicotine on two occasions separated by a wash-out period of at least 1 week. Blood samples were collected at baseline and at 15 and 60 min following exposure and analysed with the Total-Thrombus-formation analysis system evaluating fibrin-rich thrombus formation and platelet thrombus formation in whole blood under flow. Microvascular function was assessed at baseline and 30 min after exposure by laser speckle contrast imaging and iontophoresis of acetylcholine and sodium nitroprusside (SNP) to evaluate the endothelium-dependent and independent pathways of vasodilation. Compared with nicotine free EC aerosol, exposure to EC aerosol with nicotine significantly increased platelet thrombus formation and fibrin-rich thrombus formation at 15 min (p = 0.017 and p = 0.037, respectively) with normalisation after 60 min. Peak SNP-mediated microvascular perfusion, i.e. endothelium-independent vasodilation, was reduced following EC vaping with nicotine compared with baseline (p = 0.006). Thirty puffs of EC aerosol with nicotine increased platelet and fibrin-dependent thrombus formation and reduced microvascular dilatation capacity. No compelling effects of EC vaping without nicotine were observed, indicating nicotine as the main effector. Trial registration: ClinicalTrials.gov Identifier: NCT04175457 URL: https://clinicaltrials.gov/ct2/show/NCT04175457

Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site

POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH(2)OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (K(i)=11.8–0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, k(on)=(2.43±0.12)×10(5) M(−1)·s(−1), whereas the inhibitor with a CN group exhibited the fastest binding, k(on)=(12.0±0.08)×10(5) M(−1)·s(−1). In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH(2)OH and CHO groups had much longer half-lives of dissociation (over 5 h) compared with the compound with the CN group (25 min), although the K(i) values of the compounds were relatively similar. A possibility to optimize the duration of inhibition by changing the functional group at the P1 site is important when planning therapeutically useful POP inhibitors

Chroman-4-one- and Chromone-Based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells

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