A novel approach of combining conventional IR spectroscopy (IR) and at. force microscopy (AFM) is presented to better understand the behavior of a drug adsorbed on a metal substrate at the nanoscale level.Tip-enhanced IR nanospectroscopy (TEIRA) was used for the first time to investigate Lu AA33810, a selective brain-penetrating Y5 receptor antagonist, after immobilization on gold nanoparticles (GNPs).Here, a gold coated AFM tip and gold substrate were used to obtain the near-field electromagnetic field trapping effect.Because of the huge signal enhancement, it was possible to obtain the spectral information regarding the self-assembled monolayer of the investigated mol.The effect of two orthogonal polarizations (p- and s-polarization modulations) of the excitation laser beam on the spectral patterns is also discussed.The results show that there is a strong relationship between the state of polarization of the incident radiation and the relative IR band intensities.Another factor affecting the observed spectral differences is the topol. of the metal substrate, which may result in the induction of a cross-polarization effect.The performed anal. indicates that the C-C bond from the cyclohexyl group is oriented almost parallel to the metal surface.Conversely, the p- and s-polarized spectral variations suggest that the O=S=O angle is high enough to enable the simultaneous interaction of both oxygen atoms with the GNPs. [Figure not available: see fulltext.].

17 Aug 2017·The Journal of Physical Chemistry C

Monitoring the Interfacial Behavior of Selective Y5 Receptor Antagonist on Colloidal Gold Nanoparticle Surfaces: Surface-Enhanced Vibrational Spectroscopy Studies

Author: Piergies, Natalia ; Domin, Helena ; Pięta, Ewa ; Oćwieja, Magdalena ; Paluszkiewicz, Czesława ; Bielańska, Elżbieta ; Kwiatek, Wojciech M.

This report describes the first detailed characterization of the mol. structure of Lu AA33810, a selective Y5 receptor antagonist, and its behavior at the solid/liquid interface after conjugation with gold nanoparticles (GNPs).Physicochem. characterization, including imaging by SEM as well as electrophoretic mobility and dynamic light scattering measurements, was performed to determine the morphol., electrokinetic properties and range of stability of the GNPs.A comprehensive vibrational anal., employing Raman spectroscopy, Fourier transform IR absorption, surface-enhanced Raman spectroscopy, and surface-enhanced IR absorption methods, is reported.The exptl. data are supported by d. functional theory calculationsIt is implied that the Thz and Phe rings determine the adsorption geometry of Lu AA33810 on the studied GNPs and adopt a tilted orientation, exposing the interaction between the Thz free electron pair and the metallic nanosubstrates.The anal. also provides evidence for strong interaction between the free electron pairs located on the oxygen atoms of the SO₂ fragment of methanesulfonamide and the GNPs.The results provide important insight into designing new compounds with agonistic or antagonistic properties toward the Y5 receptor.

01 Feb 2017·PsychopharmacologyQ3 · MEDICINE

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

Q3 · MEDICINE

Article

Author: Szewczyk, Bernadeta ; Domin, Helena ; Woźniak, Monika ; Śmiałowska, Maria ; Pochwat, Bartłomiej

RATIONALEIt has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.OBJECTIVEIn the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.RESULTSWe observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810.CONCLUSIONOur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.

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Nervous System Diseases	Preclinical	-	H. Lundbeck A/S	-

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