Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism.
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ABSTRACT:
SUBMITTER: Dosa PI
PROVIDER: S-EPMC3629922 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Serotonin [5-hydroxytryptamine (5-HT)] released from mast cells or platelets in peripheral tissues is one of the important inflammatory mediators in pain and hyperalgesia. The involvement of 5-HT in pain is complex because it could inhibit or facilitate nociceptive transmission, reflecting the presence of multiple 5-HT subtype receptors on peripheral and central nociceptors. The present study aimed to investigate the involvement of 5-HT(2B) in 5-HT-induced pain and whether the subtype exists in dorsal root ganglion (DRG) neurons. Injecting the 5-HT or 5-HT(2) agonist in hindpaws of mice induced significant hyperalgesia to mechanical stimuli, which was inhibited by the 5-HT(2B/2C) antagonist but not by 5-HT(1A), 5-HT(2A), or 5-HT(3A) antagonists. Therefore, 5-HT(2B) or 5-HT(2C) may be involved in 5-HT-induced mechanical hyperalgesia. The 5-HT(2B/2C) antagonist also blocked 5-HT-induced transient [Ca(2+)] signaling in DRG neurons. All subtypes of 5-HT receptors except 5-HT(2C) and 5-HT(6) are present in DRGs. In situ hybridization also demonstrated 5-HT(2B) mainly expressed in small- to medium-diameter DRG neurons that respond to pain. Likely, 5-HT(2B) mediates 5-HT-induced mechanical hyperalgesia in mice.
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Project description:Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.
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Project description:Transcriptome quality control is an important step in RNA-Seq experiments. However, the quality of de novo assembled transcriptomes is difficult to assess, due to the lack of reference genome to compare the assembly to. We developed a method to assess and improve the quality of de novo assembled transcriptomes by focusing on the removal of chimeric sequences. These chimeric sequences can be the result of faulty assembled contigs, merging two transcripts into one. The developed method is incorporated into a pipeline, which we named Bellerophon, that is broadly applicable and easy to use. Bellerophon first uses the quality assessment tool TransRate to indicate the quality, after which it uses a transcripts per million (TPM) filter to remove lowly expressed contigs and CD-HIT-EST to remove highly identical contigs. To validate the quality of this method, we performed three benchmark experiments: (1) a computational creation of chimeras, (2) identification of chimeric contigs in a transcriptome assembly, (3) a simulated RNA-Seq experiment using a known reference transcriptome. Overall, the Bellerophon pipeline was able to remove between 40% and 91.9% of the chimeras in transcriptome assemblies and removed more chimeric than nonchimeric contigs. Thus, the Bellerophon sequence of filtration steps is a broadly applicable solution to improve transcriptome assemblies.
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Project description:In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPγS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf. Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.
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Project description:ObjectiveStructurally-improved GIP analogs were developed to determine precisely whether GIP receptor (GIPR) agonism or antagonism lowers body weight in obese mice.MethodsA series of peptide-based GIP analogs, including structurally diverse agonists and a long-acting antagonist, were generated and characterized in vitro using functional assays in cell systems overexpressing human and mouse derived receptors. These analogs were characterized in vivo in DIO mice following acute dosing for effects on glycemic control, and following chronic dosing for effects on body weight and food intake. Pair-feeding studies and indirect calorimetry were used to survey the mechanism for body weight lowering. Congenital Gipr-/- and Glp1r-/- DIO mice were used to investigate the selectivity of the agonists and to ascribe the pharmacology to effects mediated by the GIPR.ResultsNon-acylated, Aib2 substituted analogs derived from human GIP sequence showed full in vitro potency at human GIPR and subtly reduced in vitro potency at mouse GIPR without cross-reactivity at GLP-1R. These GIPR agonists lowered acute blood glucose in wild-type and Glp1r-/- mice, and this effect was absent in Gipr-/- mice, which confirmed selectivity towards GIPR. Chronic treatment of DIO mice resulted in modest yet consistent, dose-dependent decreased body weight across many studies with diverse analogs. The mechanism for body weight lowering is due to reductions in food intake, not energy expenditure, as suggested by pair-feeding studies and indirect calorimetry assessment. The weight lowering effect was preserved in DIO Glp-1r-/- mice and absent in DIO Gipr-/- mice. The body weight lowering efficacy of GIPR agonists was enhanced with analogs that exhibit higher mouse GIPR potency, with increased frequency of administration, and with fatty-acylated peptides of extended duration of action. Additionally, a fatty-acylated, N-terminally truncated GIP analog was shown to have high in vitro antagonism potency for human and mouse GIPR without cross-reactive activity at mouse GLP-1R or mouse glucagon receptor (GcgR). This acylated antagonist sufficiently inhibited the acute effects of GIP to improve glucose tolerance in DIO mice. Chronic treatment of DIO mice with high doses of this acylated GIPR antagonist did not result in body weight change. Further, co-treatment of this acylated GIPR antagonist with liraglutide, an acylated GLP-1R agonist, to DIO mice did not result in increased body weight lowering relative to liraglutide-treated mice. Enhanced body weight lowering in DIO mice was evident however following co-treatment of long-acting selective individual agonists for GLP-1R and GIPR, consistent with previous data.ConclusionsWe conclude that peptide-based GIPR agonists, not peptide-based GIPR antagonists, that are suitably optimized for receptor selectivity, cross-species activity, and duration of action consistently lower body weight in DIO mice, although with moderate efficacy relative to GLP-1R agonists. These preclinical rodent pharmacology results, in accordance with recent clinical results, provide definitive proof that systemic GIPR agonism, not antagonism, is beneficial for body weight loss.
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Project description:BackgroundThis study evaluated the effects on healthcare access inequities of an intervention exempting children under 5 years from user fees in Burkina Faso.MethodsThe design consisted of two complementary studies. The first was an interrupted time series (56 months before and 12 months after) study of daily curative consultations according to distance (<5, 5-9 and ?10 km) in a stratified random sample of 18 health centres: 12 with the intervention and 6 without. The second was a household panel survey (n=1214) assessing the evolution of health-seeking behaviours. Multilevel regression was used throughout.ResultsAttendance doubled under the intervention, after adjusting for Centres de Santé et de Promotion Sociale size, districts, secular trend and seasonal variation. Utilisation increased for all distance ranges and in all of the 12 health centres of the intervention area. The exemption benefited all children (rate ratios (RR)=1.52 (1.23 to 1.88)), whether their health needs were high (RR=1.69 (1.22 to 2.32)) or not (RR=1.46 (1.10 to 1.93)) and whether the children lived near (RR=1.42 (1.09 to 1.85)) or far from a health centre (RR=1.79 (1.31 to 2.43)). The exemption benefited the children of poor families when health need was high and services near (RR=5.23; (1.30 to 20.99)). The amount saved for a child's treatment by the exemption was on average and median 2500 F CFA (?US$5).ConclusionsExempting children under five from user fees is effective and helps reduce inequities of access. It benefits vulnerable populations, although their service utilisation remains constrained by limitations in geographic accessibility of services.
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Project description:A facile synthesis for novel loperamide analogs as potential μ opioid receptors is described. The synthetic procedure for compound 5, which contains two 4-phenyl piperidine scaffolds, was optimized, and this compound was synthesized in excellent yield. We also describe a mild and highly efficient protocol for the synthesis of compounds 6 and 7.
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Project description:G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.
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