Anisotropy and NMR spectroscopy

Abstract: In this paper, different aspects concerning anisotropy in Nuclear Magnetic Resonance (NMR) spectroscopy have been reviewed. In particular, the relevant theory has been presented, showing how anisotropy stems from the dependence of internal nuclear spin interactions on the molecular orientation with respect to the external magnetic field direction. The consequences of anisotropy in the use of NMR spectroscopy have been critically discussed: on one side, the availability of very detailed structural and dynamic information, and on the other side, the loss of spectral resolution. The experiments used to measure the anisotropic properties in solid and soft materials, where, in contrast to liquids, such properties are not averaged out by the molecular tumbling, have been described. Such experiments can be based either on static low-resolution techniques or on one- and two-dimensional pulse sequences exploiting Magic Angle Spinning (MAS). Examples of applications of NMR spectroscopy have been shown, which exploit anisotropy to obtain important physico-chemical information on several categories of systems, including pharmaceuticals, inorganic materials, polymers, liquid crystals, and self-assembling amphiphiles in water. Solid-state NMR spectroscopy can be considered, nowadays, one of the most powerful characterization techniques for all kinds of solid, either amorphous or crystalline, and semi-solid systems for the obtainment of both structural and dynamic properties on a molecular and supra-molecular scale. Graphic abstract: [Figure not available: see fulltext.

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects

A cell surface arabinogalactan-peptide influences root hair cell fate

Indexación: Scopus.Root hairs (RHs) develop from specialized epidermal trichoblast cells, whereas epidermal cells that lack RHs are known as atrichoblasts. The mechanism controlling RH cell fate is only partially understood. RH cell fate is regulated by a transcription factor complex that promotes the expression of the homeodomain protein GLABRA 2 (GL2), which blocks RH development by inhibiting ROOT HAIR DEFECTIVE 6 (RHD6). Suppression of GL2 expression activates RHD6, a series of downstream TFs including ROOT HAIR DEFECTIVE 6 LIKE-4 (RSL4) and their target genes, and causes epidermal cells to develop into RHs. Brassinosteroids (BRs) influence RH cell fate. In the absence of BRs, phosphorylated BIN2 (a Type-II GSK3-like kinase) inhibits a protein complex that regulates GL2 expression. Perturbation of the arabinogalactan peptide (AGP21) in Arabidopsis thaliana triggers aberrant RH development, similar to that observed in plants with defective BR signaling. We reveal that an O-glycosylated AGP21 peptide, which is positively regulated by BZR1, a transcription factor activated by BR signaling, affects RH cell fate by altering GL2 expression in a BIN2-dependent manner. Changes in cell surface AGP disrupts BR responses and inhibits the downstream effect of BIN2 on the RH repressor GL2 in root epidermis. © 2020 The Authors. New Phytologist © 2020 New Phytologist Trusthttps://nph-onlinelibrary-wiley-com.recursosbiblioteca.unab.cl/doi/10.1111/nph.1648

Mechanisms Used for Genomic Proliferation by Thermophilic Group II Introns

Studies of mobile group II introns from a thermophilic cyanobacterium reveal how these introns proliferate within genomes and might explain the origin of introns and retroelements in higher organisms

Detailed Characterization of the Dynamics of Ibuprofen in the Solid State by a Multi-Technique NMR Approach

The internal rotations and interconformational jumps of ibu- profen in the solid state are fully characterized by the simulta- neous analysis of a variety of low- and high-resolution NMR ex- periments for the measurement of several 13C and 1H spectral and relaxation properties, performed at different temperatures and, in some cases, frequencies. The results are first qualitative- ly analyzed to identify the motions of the different molecular fragments and to assign them to specific frequency ranges (slow, 106 Hz). In a second step, a simultaneous fit of the experimental data sets most sensitive to each frequency range is performed by means of suitable motional models to obtain, for each motion, values of correlation times and activation energies. The rotations of the three methyl groups around their ternary symmetry axes, which occur in the fast regime, are characterized by slightly different activation energies. Thanks to the simultaneous analy- sis of 1H and 13C data, the p-flip of the dimeric structure made by the acidic groups is also identified and seen to occur in the fast regime. On the contrary, the p-flip of the phenyl ring is found to occur in the slow motional regime, while the rota- tions of the isobutyl and propionic groups are frozen. The ap- proach used appears to be of general applicability for studying the dynamics of small organic molecules

13C Chemical Shielding Tensors: A Combined Solid-State NMR and DFT Study of the Role of Small-Amplitude Motions

Nuclear chemical shielding tensors (CSTs) provide valuable information on structural and dynamic properties of molecular fragments in the solid state, and they are often exploited to obtain a detailed character- ization of reorientational or interconformational motions in the kilohertz regime. In this work, we introduce a new combined computational DFT and experimental solid-state NMR approach to investigate the effects of small- amplitude vibrational motions on 13C CSTs. This approach was tested on ibuprofen, for which the influence of reorientational motions on CSTs could be ruled out from a previous detailed investigation of its dynamic properties. The data relative to the carbons belonging to the phenyl moiety were analyzed and discussed in terms of phenyl ring librations and in-plane and out-of-plane CH bendings

Dynamics of Clay-Intercalated Ibuprofen Studied by Solid State Nuclear Magnetic Resonance

In designing drug delivery systems with improved release properties and bioavailability, the dynamic features of the active pharmaceutical ingredient can be crucial for the final product properties. In this work, we aimed at obtaining the first characterization of the molecular dynamic properties of one of the most common nonsteroidal anti-inflammatory drug, ibuprofen, intercalated in hydrotalcite, an interesting inorganic carrier. By exploiting a variety of solid state NMR techniques, including H-1 and C-13 MAS spectra and T-1 relaxation measurements, performed at variable temperature and carrying out a synergic analysis of all results, it has been possible to ascertain that the mobility of ibuprofen within the carrier is remarkably increased. In particular, strong indications have been obtained that ibuprofen molecules, in addition to internal interconformational dynamics, experience an overall molecular motion. Also considering that ibuprofen is "anchored" to the charged surface of the hydrotalcite layers through its carboxylate moiety, such motion could be a wobbling-in-a-cone. Activation energies and correlation times of all the motions of intercalated ibuprofen have been determined

Translational and rotational diffusion of three glass forming alcohols by 1H field cycling NMR relaxometry

1H field-cycling NMR relaxometry was applied to investigate the dynamics of the three glass forming alcohols 2-phenylbutan-1-ol (BEP), 2-(trifluoromethyl)phenetyl alcohol (2TFMP), and 4-(trifluoromethyl)phenetyl alcohol (4TFMP), all having a phenyl ring as substituent. 1H longitudinal relaxation rates, R1, were measured at Larmor frequencies (ν) from 0.01 to 35 MHz in the liquid phase of the three alcohols between 213 and 313 K. Data analysis was performed using master curves built on the basis of the frequency temperature superposition principle exploiting the NMR susceptibility representation. Longitudinal relaxation was considered to arise from two dynamic processes, i.e. translational diffusion and molecular rotations. For the first process a force-free hard-sphere model was used, whereas the phenomenological Davidson-Cole function was employed to model the second motional process. The analysis allowed translational and rotational correlation times to be determined over a wide time scale (10−11 - 10−3 s). The ratio between the two correlation times indicated the formation of hydrogen bonded networks for all alcohols, while their trends with temperature suggested that BEP forms stronger hydrogen bonds. The resulting self-diffusion coefficients were in agreement with the values independently determined from the slope of R1 vs ν1/2 at low frequencies