1,721,109 research outputs found
A Convenient Route to Enantiomerically Pure 2-Substituted Methyl Glycerate Derivatives
No full textThe lithium enolate of a butanediacetal-protected glycerate derivative undergoes efficient and diastereoselective alkylation to afford a new
fully substituted stereogenic center. These compounds may be elaborated to stable 2-substituted glyceraldehyde derivatives
The novel nociceptin/orphanin FQ receptor antagonist Trap-101 alleviates experimental parkinsonism through inhibition of the nigro-thalamic pathway. Positive interaction with L-DOPA
No full textIn this study we investigated whether the recently discovered antagonist of the nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor, 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101) changed motor activity in naïve rats and mice, and alleviated parkinsonism in 6-hydroxydopamine hemilesioned rats. In naïve rats, Trap-101 stimulated motor activity at 10 mg/Kg and inhibited it at 30 mg/Kg. Such dual action was also observed in wild-type but not NOP receptor knockout mice suggesting specific involvement of NOP receptors. Trap-101 alleviated akinesia/bradykinesia and improved overall gait ability in hemiparkinsonian rats, being effective starting at 1 mg/Kg and without worsening motor deficit at 30 mg/Kg. To investigate the circuitry involved in the Trap-101 action, behavioral tests were performed in rats undergoing microdialysis. The anti-akinetic/anti-bradykinetic effects of Trap-101, given systemically (10 mg/Kg) or perfused in substantia nigra reticulata (10 muM), were associated with reduced glutamate and enhanced GABA release in substantia nigra, and reduced GABA release in ipsilateral ventro-medial thalamus. When combined with ineffective doses of l-DOPA (0.1 mg/Kg), Trap-101 evoked larger neurochemical and behavioral responses. These data show that Trap-101 is an effective NOP receptor antagonist in vivo and confirm that NOP receptor antagonists alleviate parkinsonism through blockade of nigral NOP receptors and impairment of nigro-thalamic transmission
Synthesis and biological properties of C-terminal vinyl ketone pseudotripeptides
No full textThe ubiquitin-proteasome pathway responsible for the turnover of many cellular proteins represents an attractive target in the development of new drug therapies: In particular, modulation of the proteasome activity by specific inhibitors may represent a useful tool for the treatment of tumours. Here, we report synthesis and activity of a new series of oligopseudopeptide analogues bearing a vinyl ketone pharmacophoric unit at the C-terminal position. Some derivatives showed inhibition in the mu M range of the trypsin-like (T-L) active site of the proteasome
Synthetic cannabinoid JWH-018 impairs object recognition memory in mice: behavioral and electrophysiological evidence
No full textIntroduction:
JWH-018 (1-pentyl-3-(1-naphthoyl) indole) is a synthetic CB1 and CB2 agonist illegally marketed in 'Spice' and “herbal blend” for its psychoactive effects similar to those produced by Cannabis. In rodents JWH-018 reproduces the typical effects of THC as hypothermia, analgesia, hypolocomotion and akinesia, while its effects on memory functions are still unknowns. Behavioral and in vitro electrophysiological studies were undertaken to investigated the effects of acute JWH-018 administration on novel object recognition memory and hippocampal LTP formation in CD-1 male mice.
Methods and Results:
The novel object recognition task is a one-trial learning paradigm allowing the assessment of acquisition, consolidation or retrieval of (object) information separately. JWH-018 (0.1-1 mg/Kg i.p.) dose-dependently impaired both short (2 hours after training section) and long (24 hours after training section) memory retention in mice by CB1 receptor stimulation, since JWH-018 effect was prevented by the selective CB-1 receptor antagonist AM251 (3 mg/Kg).
Electrically evoked Schaffer area fEPSP has been extracellularly recorded from stratum radiatum of mouse dorsal hippocampal transversal slices. A stimulus–response curve was recorded before and after JWH-018 contact. At this time, an LTP stimulation paradigm was applied. JWH-018 (10-1000 nM) dose-dependently reduced LTP in hippocampal slices and abolished it at higher concentrations (300 and 1000 nM).
Conclusion:
These results show that JWH-018 impairs cognitive function in mice possibly by impairing hippocampal memory formation. This aspect should be carefully investigated since chronic consumption of THC impairs cognitive function not only in animal models but in particular in human consumers by altering brain neurodevelopment (http://www.dronet.org/monografia.php?monografie=93)
P3 and P4 position analysis of vinyl ester pseudopeptide proteasome inhibitors
No full textTwo small libraries of tripeptidic-based vinyl ester derivative proteasome inhibitors were synthesized and tested, starting
with the Hmb-Val-Gln-Leu-VE prototype. The P3 and P4 positions were investigated with a complete set of amino acid residues,
some of which showed remarkable selective inhibition of the trypsin-like (b2) subunit. In both positions, aromatic and hydrophobic
residues were preferred
1-Benzyl-N-[3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) antagonizes NOP receptor-mediated potassium channel activation in rat periaqueductal gray slices
No full textNociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor, the fourth member of opioid receptor family, shares 60-70% homology with traditional opioid receptors but displays little affinity for opioids. This receptor was implicated in many neurological functions and its functional heterogeneity has been proposed. Therefore, it is imperative to develop and characterize new ligands for NOP receptors. 1-Benzyl-N-[3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) is a new non-peptide ligand of NOP receptor having antagonistic actions in cloned and peripheral NOP receptors. In this study, we quantitatively characterized its effect on the native NOP receptors in the midbrain slices containing ventrolateral periaqueductal gray (vlPAG), a region with dense NOP receptors and involved in pain regulation. In vlPAG neurons, N/OFQ induced G-protein-coupled inwardly rectifying potassium (GIRK) current through NOP receptors. Compound 24, at 0.3-10 μM, attenuated N/OFQ-induced GIRK current concentration-dependently. The antagonistic potency of Compound 24 in vlPAG neurons (IC50: 2.6 ± 0.6 μM) was, however, lower than that obtained in mouse vas deferens preparations or expressed human NOP receptors. The action kinetic of Compound 24 was slower than [Nphe1, Arg14, Lys15]N/OFQ-NH2 (UFP-101), a peptide antagonist, in the same preparation. Compound 24 had no intrinsic agonistic activity at NOP receptors at the concentration up to 10 μM. However, at concentrations higher than 3 μM, it also attenuated the GIRK current induced by [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, a mu-opioid receptor agonist. It is concluded that Compound 24 acts as a pure antagonist at the native NOP receptors in the vlPAG with moderate potency and selectivity. © 2009 Elsevier B.V. All rights reserved
Letter to the Editor: Antimicrobial properties of mucus from the brown garden snail Helix aspersa
No full textComment on "Antimicrobial properties of mucus from the brown garden snail Helix aspersa.
Use of N-(3-oxo-dodecanoil)-l-omoserina lattone (3-oxo-C12-HSL), (S)-4-(2-(2-metossietossi)etossi)-3-oxo-omoserina lattone and derivatives to modulate HLA-G molecule expression
No full textLa presente invenzione riguarda l’utilizzo delle molecole N-(3-oxo-dodecanoil)-l-omoserina lattone (3-oxo-C12-HSL), (S)-4-(2-(2-metossietossi)etossi)-3-oxo-omoserina lattone e derivati per modulare l’espressione della molecola HLA-G da parte di cellule umane. In accordo con l’invenzione, le molecole N-(3-oxo-dodecanoil)-l-omoserina lattone (3-oxo-C12-HSL), (S)-4-(2-(2-metossietossi)etossi)-3-oxo-omoserina lattone e derivati sono utilizzati su cellule umane (cellule del sangue, cellule da tessuti) per modulare HLA-G, al fine di svolgere un’azione tollerogenica ed anti-infiammatoria. L’invenzione offre una composizione farmaceutica per l’utilizzo di tali composti a scopi terapeutici
Synthesis and biological evaluation of new vinyl ester pseudotripeptide proteasome inhibitors
No full textHere we report the synthesis and biological activities of new tripeptidic-based vinyl ester derivative proteasome inhibitors. Starting from Hmb-Val-Ser-Leu-VE prototype, we investigated P2 position and N-terminal substitution. The more effective inhibitors of the series showed remarkable inhibition and selectivity for the trypsin-like (beta2) subunit and were revealed to be specific for the proteasome. In vitro metabolic stability studies of the new vinyl ester analogues are also reported here
‐DOPA
No full textIn this study we investigated whether the recently discovered antagonist of the nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor, 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101) changed motor activity in naïve rats and mice, and alleviated parkinsonism in 6-hydroxydopamine hemilesioned rats. In naïve rats, Trap-101 stimulated motor activity at 10 mg/Kg and inhibited it at 30 mg/Kg. Such dual action was also observed in wild-type but not NOP receptor knockout mice suggesting specific involvement of NOP receptors. Trap-101 alleviated akinesia/bradykinesia and improved overall gait ability in hemiparkinsonian rats, being effective starting at 1 mg/Kg and without worsening motor deficit at 30 mg/Kg. To investigate the circuitry involved in the Trap-101 action, behavioral tests were performed in rats undergoing microdialysis. The anti-akinetic/anti-bradykinetic effects of Trap-101, given systemically (10 mg/Kg) or perfused in substantia nigra reticulata (10 muM), were associated with reduced glutamate and enhanced GABA release in substantia nigra, and reduced GABA release in ipsilateral ventro-medial thalamus. When combined with ineffective doses of l-DOPA (0.1 mg/Kg), Trap-101 evoked larger neurochemical and behavioral responses. These data show that Trap-101 is an effective NOP receptor antagonist in vivo and confirm that NOP receptor antagonists alleviate parkinsonism through blockade of nigral NOP receptors and impairment of nigro-thalamic transmission
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