Benzylideneoxymorphone: A New Lead for Development of Bifunctional Mu/Delta Opioid Receptor Ligands

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands

CD73 (ecto‐5′‐nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory‐denk body formation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100334/1/hep26525.pd

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Structure, function and diversity of the healthy human microbiome

Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis of the HMPdata was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University

The Influence of an Acute Bout of Aerobic Exercise on Vascular Endothelial Function in Moderate Stages of Chronic Kidney Disease

Chronic kidney disease (CKD) is directly influenced by the deleterious effects of systemic inflammation and oxidative stress. The vascular endothelium may transiently respond to aerobic exercise and improve post-exercise vascular renal function in moderate stages of CKD. Brachial artery flow-mediated dilation (FMD) is a nitric-oxide-dependent measure of endothelial function that is transiently potentiated by exercise. The purpose of the study was to determine the acute influence of a single bout of high-intensity interval exercise (HIIE) or steady-state moderate-intensity exercise (SSE) on endothelial dysfunction in moderate stages of CKD. Twenty participants (n = 6 men; n = 14 women) completed 30 min of SSE (65%) and HIIE (90:20%) of VO2reserve in a randomized crossover design. FMD measurements and blood samples were obtained before, 1 h, and 24 h post-exercise. FMD responses were augmented 1 h post-exercise in both conditions (p < 0.005). Relative to pre-exercise measures, total antioxidant capacity increased by 4.3% 24 h post-exercise (p = 0.012), while paraoxonase-1 was maintained 1 h and elevated by 6.1% 24 h after SSE, but not HIIE (p = 0.035). In summary, FMD can be augmented by a single episode of either HIIE or SSE in moderate stages of CKD. Modest improvements were observed in antioxidant analytes, and markers of oxidative stress were blunted in response to either SSE or HIIE

Rapid Synthesis of Boc-2′,6′-dimethyl‑l‑tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics

The unnatural amino acid 2′,6′-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2′,6′-dimethyl-l-tyrosine (<b>3a</b>) utilizing a microwave-assisted Negishi coupling for the key carbon–carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (<b>3c</b>, <b>3d</b>, <b>3f</b>) have not previously been examined as Tyr¹ replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR)

Asymmetric Synthesis and in Vitro and in Vivo Activity of Tetrahydroquinolines Featuring a Diverse Set of Polar Substitutions at the 6 Position as Mixed-Efficacy μ Opioid Receptor/δ Opioid Receptor Ligands

We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure–activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (<b>10j</b>, <b>10k</b>, <b>10m</b>, and <b>10n</b>) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for <b>10j</b>, <b>10k</b>, <b>10m</b>, and <b>10n</b> are also reported and show the antinociceptive potency and duration of action of compounds <b>10j</b> and <b>10m</b> to be comparable to those of morphine

Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy

In an effort to expand the structure–activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the <i>o-</i> or <i>m-</i>positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the <i>p</i>-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of <b>8c</b>, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ‑Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through <i>N</i>-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (<b>14a</b>) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h

Tackling the burden of injury in Australasia : developing a binational trauma registry

Existing trauma registries in Australia and New Zealand play an important role in monitoring the management of injured patients. Over the past decade, such monitoring has been translated into changes in clinical processes and practices. Monitoring and changes have been ad hoc, as there are currently no Australasian benchmarks for “optimal” injury management. A binational trauma registry is urgently needed to benchmark injury management to improve outcomes for injured patients