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We report solid-state Cl NMR spectra in three hexachlorides, (NH)SeCl, (NH)TeCl and RbTeCl. The C(Cl) quadrupole coupling constants in the three compounds were found to be 41.4±0.1 MHz, 30.3±0.1 MHz and 30.3±0.1 MHz, respectively, some of the largest C(Cl) quadrupole coupling constants ever measured in polycrystalline powdered solids directly via Cl NMR spectroscopy. The Cl EFG tensors are axial in all three cases reflecting the C point group symmetry of the chlorine sites. Cl NMR experiments in these compounds were only made possible by employing the WURST-QCPMG pulse sequence in the ultrahigh magnetic field of 21.1 T. Cl NMR results agree with the earlier reported Cl NQR values and with the complementary plane-wave DFT calculations. The origin of the very large C(Cl) quadrupole coupling constants in these and other main-group chlorides lies in the covalent-type chlorine bonding. The ionic bonding in the ionic chlorides results in significantly reduced C(Cl) values as illustrated with triphenyltellurium chloride PhTeCl. The high sensitivity of Cl NMR to the chlorine coordination environment is demonstrated using tetrachlorohydroxotellurate hydrate K[TeCl(OH)]∙0.5HO as an example. Te MAS NMR experiments were performed for tellurium compounds to support Cl NMR findings. [ABSTRACT FROM AUTHOR]

Background: Elinzanetant is a dual neurokinin-1,3 receptor antagonist in development for the treatment of menopausal vasomotor symptoms. The objectives of these studies were to characterize the mass balance and biotransformation of elinzanetant., Methods: In the clinical evaluation, whole blood, plasma, urine, and feces were collected from healthy fasted male volunteers (n = 6) following a single dose of 120 mg [ 14 C]-elinzanetant oral suspension for analysis of total radioactivity and metabolite profiling. In vitro reaction phenotyping and kinetics experiments on enzymes involved in elinzanetant metabolism were performed., Results: On average, 90.8% of the total radioactivity administered was recovered in excreta over 480 h, mostly via the fecal route (feces 90.4%; urine 0.4%). Elinzanetant was rapidly absorbed and extensively metabolized but remained the main circulating species in plasma, accounting for 39.1% of total radioactivity. Known principal and active metabolites M27, M30/34, and M18/21 accounted for 7.6%, 13.7%, and 4.9% of total radioactivity in plasma, respectively. All other radiolabeled plasma components were each < 3.5%, revealing the oxidation product M30/34 as the only metabolite with relevant exposure (> 10% of total radioactivity). In feces, metabolites resulting from oxidative biotransformation accounted, in sum, for ~ 40% of the dose, while elinzanetant remained the primary drug-related moiety. Results of in vitro experiments indicated that metabolism of elinzanetant was primarily mediated by cytochrome P450 3A4, with minor contribution from uridine 5'-diphospho-glucuronosyltransferase., Conclusions: Elinzanetant is metabolized mainly via oxidative biotransformation mediated by cytochrome P450 3A4, and primarily excreted in feces. The primary oxidation product M30/34 is a major human metabolite of elinzanetant., Trial Registration Number: NCT04654897., Competing Interests: Declarations. Funding: This study was sponsored by NeRRe Therapeutics Ltd. (Stevenage, UK). Competing interests: Marcus-Hillert Schultze-Mosgau, Klaus Francke, Antje Rottmann, and Simone Schulz are employees of Bayer AG, Anna Engelen was an employee of Bayer AG at the time of conducting the study and data evaluation and is now an employee of Boehringer Ingelheim (Germany), Nand Singh is an employee of Quotient Science (Nottingham, UK), Steve Pawsey is an employee of NeRRe Therapeutics Ltd. (Stevenage, UK), and Ruth Lock is a consultant to NeRRe Therapeutics Ltd. and an employee of Aucuba Sciences Ltd (London, UK). Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Approval from the Research Ethics Committee was received on 14 September 2020 (IRAS ID: 285216). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Data Availability Statement: Result summaries of Bayer's sponsored clinical trials in drug development phases 1, 2, 3, and 4 are provided in the Bayer Trial Finder application after marketing authorization approval in line with the position of the global pharmaceutical industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases". In addition, results of clinical drug trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU Clinical Trials Register in line with the applicable regulations. Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials for medicines and indications approved in the United States (US) and European Union (EU) on or after January 01, 2014, as necessary for conducting legitimate research. Code Availability: Not applicable. Author Contributions: Participated in research design: Anna Engelen, Steve Pawsey, Ruth Lock, Simone I. Schulz, Nand Singh, Antje Rottmann, Marcus-Hillert Schultze-Mosgau. Conducted experiments: Anna Engelen, Steve Pawsey, Simone I. Schulz, Nand Singh. Contributed new reagents or analytic tools: Simone I. Schulz, Anna Engelen. Performed data analysis: Anna Engelen, Steve Pawsey, Simone I. Schulz, Nand Singh, Klaus Francke, Antje Rottmann, Marcus-Hillert Schultze-Mosgau. Wrote or contributed to the writing of the manuscript: all authors., (© 2024. The Author(s).)

Inorganic colloidal cesium lead halide perovskite nanocrystals (NCs) encapsulated by surface capping ligands exhibit tremendous potential in optoelectronic applications, with their surface structure playing a pivotal role in enhancing their photophysical properties. Soy lecithin, a tightly binding zwitterionic surface-capping ligand, has recently facilitated the high-yield synthesis of stable ultraconcentrated and ultradilute colloids of CsPbX 3 NCs, unlocking a myriad of potential device applications. However, the atomic-level understanding of the ligand-terminated surface structure remains uncertain. Herein, we use a versatile solid-state nuclear magnetic resonance (NMR) spectroscopic approach, in combination with dynamic nuclear polarization (DNP) and atomistic molecular dynamics (MD) simulations, to explore the effect of lecithin on the core-to-surface structures of CsPbX 3 (X = Cl or Br) perovskites, sized from micron to nanoscale. Surface-selective (cross-polarization, CP) solid-state and DNP NMR ( 133 Cs and 207 Pb) methods were used to differentiate the unique surface and core chemical environments, while the head-groups {trimethylammonium [-N(CH 3 ) 3 + ] and phosphate (-PO 4 - )} of lecithin were assigned via 1 H, 13 C, and 31 P NMR spectroscopy. A direct approach to determining the surface structure by capitalizing on the unique heteronuclear dipolar couplings between the lecithin ligand ( 1 H and 31 P) and the surface of the CsPbCl 3 NCs ( 133 Cs and 207 Pb) is demonstrated. The 1 H- 133 Cs heteronuclear correlation (HETCOR) DNP NMR indicates an abundance of Cs on the NC surface and an intimate proximity of the -N(CH 3 ) 3 + groups to the surface and subsurface 133 Cs atoms, supported by 1 H{ 133 Cs} rotational-echo double-resonance (REDOR) NMR spectroscopy. Moreover, the 1 H- 31 P{ 207 Pb} CP REDOR dephasing curve provides average internuclear distance information that allows assessment of -PO 4 - groups binding to the subsurface Pb atoms. Atomistic MD simulations of ligand-capped CsPbCl 3 surfaces aid in the interpretation of this information and suggest that ligand -N(CH 3 ) 3 + and -PO 4 - head-groups substitute Cs + and Cl - ions, respectively, at the CsCl-terminated surface of the NCs. These detailed atomistic insights into surface structures can further guide the engineering of various relevant surface-capping zwitterionic ligands for diverse metal halide perovskite NCs.

Objective: Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life., Methods: Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life., Results: Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: -3.93 [SE, 1.02], P < 0.001; week 12: -2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (-2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated., Conclusions: Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS., Competing Interests: Financial disclosure/conflicts of interest: C.C. and L.Z. are employees of Bayer CC AG. C.S. is an employee of Bayer AG. M.K., S.P., E.B., S.S., and M.T. are employees of NeRRe Therapeutics. J.B., as an employee of Cytel Inc, was a paid statistical consultant on this trial. R.A.A. has undertaken consultancy work for NeRRe Therapeutics and Sojournix Inc. J.A.S. has grant/research support from AbbVie, Inc, Bayer Healthcare LLC, Daré Bioscience, Ipsen, Mylan/Viatris Inc, Myovant Sciences, ObsEva SA, Sebela Pharmaceuticals Inc, and Viveve Medical; has been a consultant/advisory boards of Bayer HealthCare Pharmaceuticals Inc, Besins Healthcare, California Institute of Integral Studies, Camargo Pharmaceutical Services, LLC, Covance Inc, Daré Bioscience, DEKA M.E.L.A. S.r.l., Femasys Inc, KaNDy/NeRRe Therapeutics Ltd, Khyria, Madorra Pty Ltd, Mitsubishi Tanabe Pharma Development America, Inc, QUE Oncology Pty, Limited, Scynexis Inc, Sebela Pharmaceuticals, Inc, Sprout Pharmaceuticals, Inc, and Vella Bioscience Inc; has served on the Speaker's bureaus of Mayne Pharma, Inc, Myovant Sciences, Inc, Pfizer Inc, Pharmavite LLC, Scynexis Inc, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals. N.P. has undertaken consultancy and speaker's bureau work for a number of pharmaceutical companies including Bayer AG. H.J. has received grant funding from National Institutes of Health, Merck, Pfizer, and Hello Therapeutics; has undertaken consultancy work for Bayer, Jazz, and Eisai; and her spouse is an employee at Arsenal Biosciences and has equity at Merck., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Magic angle spinning nuclear magnetic resonance spectroscopy experiments are widely employed in the characterization of solid media. The approach is incredibly versatile but deleteriously suffers from low sensitivity, which may be alleviated by adopting dynamic nuclear polarization methods, resulting in large signal enhancements. Paramagnetic metal ions such as Gd 3+ have recently shown promising results as polarizing agents for 1 H, 13 C, and 15 N nuclear spins. We demonstrate that the widely available and inexpensive chemical agent Gd(NO 3 ) 3 achieves significant signal enhancements for the 13 C and 15 N nuclear sites of [2- 13 C, 15 N]glycine at 9.4 T and ∼105 K. Analysis of the signal enhancement profiles at two magnetic fields, in conjunction with electron paramagnetic resonance data, reveals the solid effect to be the dominant signal enhancement mechanism. The signal amplification obtained paves the way for efficient dynamic nuclear polarization without the need for challenging synthesis of Gd 3+ polarizing agents.

Solid-state 1 H, 13 C, and 15 N nuclear magnetic resonance (NMR) spectroscopy has been an essential analytical method in studying complex molecules and biomolecules for decades. While oxygen-17 ( 17 O) NMR is an ideal and robust candidate to study hydrogen bonding within secondary and tertiary protein structures for example, it continues to elude many. We discuss an improved multiple-turnover labeling procedure to develop a fast and cost-effective method to 17 O label fluoroenylmethyloxycarbonyl (Fmoc)-protected amino acid building blocks. This approach allows for inexpensive ($0.25 USD/mg) insertion of 17 O labels, an important barrier to overcome for future biomolecular studies. The 17 O NMR results of these building blocks and a site-specific strategy for labeled N -acetyl-MLF-OH and N-formyl-MLF-OH tripeptides are presented. We showcase growth in NMR development for maximizing sensitivity gains using emerging sensitivity enhancement techniques including population transfer, high-field dynamic nuclear polarization, and cross-polarization magic-angle spinning cryoprobes.

Context: The ideal therapy for endometriosis (EM) and uterine fibroids (UFs) would suppress estrogenic drive to the endometrium and myometrium, while minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target., Objective: This work aimed to assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women., Methods: A randomized, single-blinded, placebo-controlled study was conducted in 33 women who attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3 or 4, 9 or 10, 15 or 16, and 21 or 22 to measure serum reproductive hormones. In cycle 2, women were randomly assigned to receive once-daily oral elinzanetant 40, 80, 120 mg, or placebo (N = 8 or 9 per group)., Results: Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: -141.4 pmol/L, P = .038), and luteal-phase progesterone (120 mg change from baseline on day 21 or 22: -19.400 nmol/L, P = .046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P = .023). Elinzanetant reduced the proportion of women with a luteal-phase serum progesterone concentration greater than 30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P = .002). Treatment did not produce vasomotor symptoms., Conclusion: NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120-mg dose lowering estradiol to potentially ideal levels for UFs and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone-driven disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: To evaluate the safety, pharmacokinetics, and preliminary efficacy of NT-814, a dual neurokinin 1,3 antagonist, in postmenopausal women with vasomotor symptoms (hot flashes)., Methods: We completed a double-blind, randomized, placebo-controlled trial in three US clinical research units in 76 postmenopausal women with moderate/severe hot flashes. Participants were randomized to 14 days of once-daily NT-814 or placebo within each of four sequential dose cohorts; 50, 100, 150, and 300 mg. Participants completed diaries of hot flash frequency and severity and waking due to night sweats before (baseline) and during treatment., Results: All prespecified efficacy parameters (24-h hot flash frequency and severity, frequency of waking due to night sweats) decreased in all groups (including placebo). Mean reduction from baseline at week 2 in moderate/severe hot flash frequency was 37% in the placebo group and, respectively, 24% (P = 0.048 vs placebo), 59% (P = 0.155), 84% (P < 0.001) and 66% (P = 0.022) in the 50 mg, 100 mg, 150 mg, and 300 mg NT-814 groups; in waking due to night sweats reduction was 20% (P = 0.059), 55% (P = 0.135), 81% (P < 0.001), and 63% (P = 0.031) in the NT-814 groups and 32% in the placebo group. The improvement with NT-814 ≥150 mg was also evident in the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, more frequently in the 300 mg group. Safety monitoring identified no concerns., Conclusions: Once-daily NT-814 (≥150 mg/d) resulted in a rapid, marked improvement in hot flashes and waking due to night sweats. No safety concerns were identified. Doses up to 300 mg were well tolerated.

Background: Grass allergen peptides are in development for the treatment of grass pollen-induced allergic rhinoconjunctivitis. A previous randomized, placebo-controlled study demonstrated that grass allergen peptides significantly improved total rhinoconjunctivitis symptom scores (TRSSs) after posttreatment challenge (PTC) to rye grass in an environmental exposure unit after 1 intervening grass pollen season (GPS1)., Objective: We sought to evaluate the efficacy/safety of 4 dosing regimens of grass allergen peptides after a second (GPS2) and third (GPS3) intervening GPS in the environmental exposure unit., Methods: Eligible subjects who were randomized in the parent study (GPS1) during the first year of recruitment were invited to participate in GPS2 and GPS3, which took place 1 and 2 years after treatment cessation, respectively. Participants were not treated further, and both participants and study personnel remained blinded. The primary efficacy end point was the change in mean TRSS (reported every 30 minutes) from GPS1 baseline to the follow-up PTC calculated across all time points over days 2 to 4 for GPS2 and across hours 1 to 3 over days 2 to 4 for GPS3. Secondary efficacy end points and safety were also assessed., Results: One hundred twenty-two and 85 participants were enrolled in GPS2 and GPS3, respectively. A numerically greater, but not statistically significant improvement from baseline in mean TRSS at PTC was observed in the group receiving one 6-nmol intradermal injection every 2 weeks for 14 weeks group compared with the placebo at GPS2 (-6.0 vs -3.6, P = .0535) and GPS3 (-6.2 vs -3.6, P = .1128). Similar findings were observed for the group receiving one 6-nmol intradermal injection every 2 weeks for 14 weeks at GPS3 (-6.4 vs -3.6, P = .0759). No adverse safety signals were detected., Conclusion: Treatment with grass allergen peptides led to an improvement in allergic rhinoconjunctivitis symptoms after 3 intervening GPSs, corresponding to up to 2 years off treatment., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Acidic zeolites are porous aluminosilicates used in a wide range of industrial processes such as adsorption and catalysis. The formation of carbocation intermediates plays a key role in reactivity, selectivity and deactivation in heterogeneous catalytic processes. However, the observation and determination of carbocations remain a significant challenge in heterogeneous catalysis due to the lack of selective techniques of sufficient sensitivity to detect their low concentrations. Here, we combine 13 C isotopic enrichment and efficient dynamic nuclear polarization magic angle spinning nuclear magnetic resonance spectroscopy to detect carbocations in zeolites. We use two dimensional 13 C- 13 C through-bond correlations to establish their structures and 29 Si- 13 C through-space experiments to quantitatively probe the interaction between multiple surface sites of the zeolites and the confined hydrocarbon pool species. We show that a range of various membered ring carbocations are intermediates in the methanol to hydrocarbons reaction catalysed by different microstructural β-zeolites and highlight that different reaction routes for the formation of both targeted hydrocarbon products and coke exist. These species have strong van der Waals interaction with the zeolite framework demonstrating that their accumulation in the channels of the zeolites leads to deactivation. These results enable understanding of deactivation pathways and open up opportunities for the design of catalysts with improved performances.

Background and Objective: The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man., Methods: 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations., Results: Single oral doses of 5-300 mg and repeated oral doses of 50-500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6-18.3 h (Day 7; Part B). V158866 reached steady state within 2-3 days of administration, with an accumulation ratio, based on AUC0-24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs., Conclusions: V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300-500 mg/day.

We demonstrate that dynamic nuclear polarization of membrane proteins in lipid bilayers may be achieved using a novel polarizing agent: pairs of spin labels covalently bound to a protein of interest interacting at an intermolecular interaction surface. For gramicidin A, nitroxide tags attached to the N-terminal intermolecular interface region become proximal only when bimolecular channels forms in the membrane. We obtained signal enhancements of sixfold for the dimeric protein. The enhancement effect was comparable to that of a doubly tagged sample of gramicidin C, with intramolecular spin pairs. This approach could be a powerful and selective means for signal enhancement in membrane proteins, and for recognizing intermolecular interfaces.