185 research outputs found
Structureâactivity relationship investigation of triazole-based kappa opioid receptor agonists
Select triazole-based small molecules possess potent and selective kappa opioid receptor (KOR) agonism. Here, we designed twenty new analogs to investigate the structureâactivity relationship effects for all three functional groups attached to the triazole core. We identified specific groups that are critical for KOR potency and further extended the range of moieties explored. These efforts revealed analogs with potency on par with our lead triazole probe molecule, Triazole 1.1, in addition to analogs possessing a spectrum of less potent KOR agonist activity
Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPÎłS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting
Abstract Differential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPÎłS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5âČGNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5âČGNTI, is presented using this approach
Potency enhancement of the Îș-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif
Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists
Gravitational Lensing at Millimeter Wavelengths
With today's millimeter and submillimeter instruments observers use
gravitational lensing mostly as a tool to boost the sensitivity when observing
distant objects. This is evident through the dominance of gravitationally
lensed objects among those detected in CO rotational lines at z>1. It is also
evident in the use of lensing magnification by galaxy clusters in order to
reach faint submm/mm continuum sources. There are, however, a few cases where
millimeter lines have been directly involved in understanding lensing
configurations. Future mm/submm instruments, such as the ALMA interferometer,
will have both the sensitivity and the angular resolution to allow detailed
observations of gravitational lenses. The almost constant sensitivity to dust
emission over the redshift range z=1-10 means that the likelihood for strong
lensing of dust continuum sources is much higher than for optically selected
sources. A large number of new strong lenses are therefore likely to be
discovered with ALMA, allowing a direct assessment of cosmological parameters
through lens statistics. Combined with an angular resolution <0.1", ALMA will
also be efficient for probing the gravitational potential of galaxy clusters,
where we will be able to study both the sources and the lenses themselves, free
of obscuration and extinction corrections, derive rotation curves for the
lenses, their orientation and, thus, greatly constrain lens models.Comment: 69 pages, Review on quasar lensing. Part of a LNP Topical Volume on
"Dark matter and gravitational lensing", eds. F. Courbin, D. Minniti. To be
published by Springer-Verlag 2002. Paper with full resolution figures can be
found at ftp://oden.oso.chalmers.se/pub/tommy/mmviews.ps.g
Development of functionally selective, small molecule agonists at kappa opioid receptors
The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and ÎČarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects ofKORactivation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through ÎČarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from ÎČarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activateGprotein coupling but weakly recruitÎČarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo
Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting
Study of the lineshape of the chi(c1) (3872) state
A study of the lineshape of the chi(c1) (3872) state is made using a data sample corresponding to an integrated luminosity of 3 fb(-1) collected in pp collisions at center-of-mass energies of 7 and 8 TeV with the LHCb detector. Candidate chi(c1)(3872) and psi(2S) mesons from b-hadron decays are selected in the J/psi pi(+)pi(-) decay mode. Describing the lineshape with a Breit-Wigner function, the mass splitting between the chi(c1 )(3872) and psi(2S) states, Delta m, and the width of the chi(c1 )(3872) state, Gamma(Bw), are determined to be (Delta m=185.598 +/- 0.067 +/- 0.068 Mev,)(Gamma BW=1.39 +/- 0.24 +/- 0.10 Mev,) where the first uncertainty is statistical and the second systematic. Using a Flatte-inspired model, the mode and full width at half maximum of the lineshape are determined to be (mode=3871.69+0.00+0.05 MeV.)(FWHM=0.22-0.04+0.13+0.07+0.11-0.06-0.13 MeV, ) An investigation of the analytic structure of the Flatte amplitude reveals a pole structure, which is compatible with a quasibound D-0(D) over bar*(0) state but a quasivirtual state is still allowed at the level of 2 standard deviations
Measurement of the CKM angle in and decays with
A measurement of -violating observables is performed using the decays
and , where the meson is
reconstructed in one of the self-conjugate three-body final states and (commonly denoted ). The decays are analysed in bins of the -decay phase space, leading
to a measurement that is independent of the modelling of the -decay
amplitude. The observables are interpreted in terms of the CKM angle .
Using a data sample corresponding to an integrated luminosity of
collected in proton-proton collisions at centre-of-mass
energies of , , and with the LHCb experiment,
is measured to be . The hadronic
parameters , , , and ,
which are the ratios and strong-phase differences of the suppressed and
favoured decays, are also reported
Measurement of CP asymmetries and branching fraction ratios of Bâ decays to two charm mesons
The asymmetries of seven decays to two charm mesons are measured using data corresponding to an integrated luminosity of of proton-proton collisions collected by the LHCb experiment. Decays involving a or meson are analysed by reconstructing only the or decay products. This paper presents the first measurement of and , and the most precise measurement of the other five asymmetries. There is no evidence of violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.The CP asymmetries of seven B decays to two charm mesons are measured using data corresponding to an integrated luminosity of 9 fb of proton-proton collisions collected by the LHCb experiment. Decays involving a D or meson are analysed by reconstructing only the D or decay products. This paper presents the first measurement of (BâD) and (BâD), and the most precise measurement of the other five CP asymmetries. There is no evidence of CP violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.[graphic not available: see fulltext]The asymmetries of seven decays to two charm mesons are measured using data corresponding to an integrated luminosity of of proton-proton collisions collected by the LHCb experiment. Decays involving a or meson are analysed by reconstructing only the or decay products. This paper presents the first measurement of and , and the most precise measurement of the other five asymmetries. There is no evidence of violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured
Helium identification with LHCb
The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using pp collision data at â(s) = 13 TeV recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of 5.5 fb-1. A total of around 105 helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately 50% with a corresponding background rejection rate of up to O(10^12). These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei
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