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- Bartuzi, Damian, et al.
(författare)
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Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
- 2022
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Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT(2A)R interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.
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- Hestbaek, A. D., et al.
(författare)
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Child welfare removal of infants: Exploring policies and principles for decision-making in Nordic countries
- 2020
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Ingår i: Children and Youth Services Review. - : Elsevier BV. - 0190-7409. ; 108
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Tidskriftsartikel (refereegranskat)abstract
- This descriptive policy analysis examines the position of infants' rights in the family service orientated child welfare systems of Denmark, Finland, Norway and Sweden when being placed in out-of-home care. Its focus is on the contexts of, and legal procedures for, removing babies from home into public care. Children under the age of one year are taken into public care mainly through voluntary and emergency measures. Analysis of the development over a decade displays big intra-country differences in the prevalence of infant removal, varying from 2 per 1000 to 8 per 1000. The scant prevalence of public policy, practice guidelines and research indicates that infant removal is in some ways an anomaly, an unspoken leaf in the Nordic child welfare systems, whereas the Nordic welfare states otherwise extensively support families with young children through universal interventions. The findings invite to a re-examination of the rights of infants and their specific needs in the welfare states in order to establish responsive and efficient child protection systems.
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- Patel, Jayendra Z., et al.
(författare)
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Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:21, s. 8484-8496
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.
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