1,721,662 research outputs found
Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation
No full textGPR88 is an orphan G protein-coupled receptor mainly
expressed
in the brain, whose endogenous ligand has not yet been identified.
To elucidate GPR88 functions, our group has developed RTI-13951-33
(1b) as the first in vivo active GPR88
agonist, but its poor metabolic stability and moderate brain permeability
remain to be further optimized. Here, we report the design, synthesis,
and pharmacological characterization of a new series of RTI-13951-33
analogues with the aim of improving pharmacokinetic properties. As
a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability
(half-life of 5.8 h) and brain permeability (brain/plasma ratio of
>1) in mice. Notably, RTI-122 was more effective than RTI-13951-33
in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark
paradigm. Collectively, our findings suggest that RTI-122 is a promising
lead compound for drug discovery research of GPR88 agonists
Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation
No full textGPR88 is an orphan G protein-coupled receptor mainly
expressed
in the brain, whose endogenous ligand has not yet been identified.
To elucidate GPR88 functions, our group has developed RTI-13951-33
(1b) as the first in vivo active GPR88
agonist, but its poor metabolic stability and moderate brain permeability
remain to be further optimized. Here, we report the design, synthesis,
and pharmacological characterization of a new series of RTI-13951-33
analogues with the aim of improving pharmacokinetic properties. As
a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability
(half-life of 5.8 h) and brain permeability (brain/plasma ratio of
>1) in mice. Notably, RTI-122 was more effective than RTI-13951-33
in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark
paradigm. Collectively, our findings suggest that RTI-122 is a promising
lead compound for drug discovery research of GPR88 agonists
Isolation and characterization of male-germ-cell transcripts in Nicotiana tabacum
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The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice
No full textInternational audienceGPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders
Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation
No full textInternational audienceGPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists
Amélioration de la stabilité métabolique de l'agoniste GPR88 RTI-13951-33 : conception, synthèse et évaluation biologique
No full textInternational audienceGPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Draft genome of the xanthan producer Xanthomonas campestris NRRL B-1459 (ATCC 13951)
No full textWibberg D, Alkhateeb R, Winkler A, et al. Draft genome of the xanthan producer Xanthomonas campestris NRRL B-1459 (ATCC 13951). Journal of Biotechnology. 2015;204:45-46.Xanthomonas campestris NRRL B-1459 was used in pioneering studies related to the biotechnological production of xanthan, the commercially most important polysaccharide of bacterial origin. The analysis of its genome revealed a 5.1 Mb chromosome plus the first complete plasmid of an X. campestris strain applied in biotechnology. (C) 2015 Elsevier B.V. All rights reserved
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