PubMed Journals Articles About "TollLike Receptor Agonists Pipeline Insights 2017 Updated 30052017" RSS

07:25 EDT 20th June 2018 | BioPortfolio

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Showing "TollLike Receptor Agonists Pipeline Insights 2017 Updated 30052017" PubMed Articles 1–25 of 14,000+

Selectivity profiling of NOP, MOP, DOP and KOP receptor antagonists in the rat spinal nerve ligation model of mononeuropathic pain.

Agonists selectively acting at NOP, MOP, DOP and KOP receptors as well as mixed opioid receptor agonists are known to exert anti-hypersensitive efficacy in the rat spinal nerve ligation (SNL) model of neuropathic pain. To investigate the relative contribution of individual opioid receptor activation to the overall efficacy of mixed opioid receptor agonists, selective doses of respective opioid receptor antagonists have to be employed. In order to identify such selective antagonist doses, doses of the select...

Antiparkinsonian and antidyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists.

We previously showed that Nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve parkinsonian disabilities and attenuate dyskinesia development and expression.

Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent.

The objective of this study was to investigate the pharmacologic characteristics of omidenepag isopropyl (OMDI), a compound developed as a novel intraocular pressure (IOP)-lowering agent, with better IOP control and fewer side effects than other prostanoid receptor agonists such as prostaglandin F receptor (FP) agonists.

Assessment of Switching to Suvorexant versus the Use of Add-on Suvorexant in Combination with Benzodiazepine Receptor Agonists in Insomnia Patients: A Retrospective Study.

Suvorexant is a novel hypnotic drug that does not interact with the conventional γ-aminobutyric acid (GABA)-A receptor. We investigated the method by which suvorexant was introduced in insomnia patients who were taking benzodiazepine receptor agonists (BzRA).

Anticancer activity study of A adenosine receptor agonists.

A adenosine receptor (AAR) signalling activation seems to mediate anticancer effect, and it has been targeted for drug development. The identification of potent and selective AAR agonists could be crucial for cancer drug development.

Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multi-dose Formulations.

Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design & synthesis, experimental ac...

Designing selective modulators for the nicotinic receptor subtypes: challenges and opportunities.

Nicotinic receptors are membrane proteins involved in several physiological processes. They are considered suitable drug targets for various CNS disorders or conditions, as shown by the large number of compounds which have entered clinical trials. In recent years, nonconventional agonists have been discovered: positive allosteric modulators, allosteric agonists, site-specific agonists and silent desensitizers are compounds able to modulate the receptor interacting at sites different from the orthodox one, o...

α7 Nicotinic Acetylcholine Receptor: A Potential Target in Treating Cognitive Decline in Schizophrenia.

The aim of this article is to review the recent trials of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists and positive allosteric modulators (PAMs) on the treatment of cognitive decline in schizophrenia. α7 Nicotinic acetylcholine receptor abnormalities in schizophrenia and clinical implications of α7 nAChR agonists and PAMs are also discussed.

A Binding Kinetics Study of Human Adenosine A3 Receptor Agonists.

The human adenosine A3 (hA3) receptor has been suggested as a viable drug target in inflammatory diseases and in cancer. So far, a number of selective hA3 receptor agonists (e.g. IB-MECA and 2-Cl-IB-MECA) inducing anti-inflammatory or anticancer effects are under clinical investigation. Drug-target binding kinetics is increasingly recognized as another pharmacological parameter, next to affinity, for compound triage in the early phases of drug discovery. However, such a kinetics-driven analysis has not yet ...

The effect of glucagon-like peptide 1 and glucagon-like peptide 1 receptor agonists on energy expenditure: a systematic review and meta-analysis.

We reviewed clinical trials addressing the effect of glucacon-like peptide 1 (GLP-1) or GLP-1 receptor agonists (GLP-1RA) on energy expenditure (EE) in adults.

Structure-Based Design, Synthesis and in vivo Antinociceptive Effects of Selective A1 Adenosine Receptor Agonists.

Our previous work discovered that combining the appropriate 5- and N6-substitution in adenosine derivatives leads to highly selective human A1 adenosine receptor (hA1AR) agonists or highly potent dual hA1AR agonists and hA3AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N6-substituted-5-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N6-(±)-endo-norbornyl derivative 12 was the most potent and selective...

Polypharmacy through Phage Display: Selection of Glucagon and GLP-1 Receptor Co-agonists from a Phage-Displayed Peptide Library.

A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequ...

Interactive effects of morphine and dopamine receptor agonists on spatial recognition memory in mice.

Both opiates and dopamine play important roles in learning and memory. Although synergistic action between these two neurotransmitters has been found, their functional roles remain unclear. Here, low dose morphine (2.5 mg/kg) and low dose dopamine receptor agonists (apomorphine: 0.05 mg/kg; SKF38393: 0.01 mg/kg; bromocriptine: 0.05 mg/kg), which have no effects on spatial recognition memory, were injected intraperitoneally into mice 30 min before a memory test in a two-trial recognition Y-maze. The Y-maze i...

Demystifying P2Y1 Receptor Ligand Recognition through Docking and Molecular Dynamics Analyses.

We performed a molecular modeling analysis of 100 nucleotide-like bisphosphates and 46 non-nucleotide arylurea derivatives previously reported as P2Y1R binders using the recently solved hP2Y1R structures. We initially docked the compounds at the X-ray structures and identified the binding modes of representative compounds highlighting key patterns in the structure-activity relationship (SAR). We subsequently subjected receptor complexes with selected key agonists (2MeSADP and MRS2268) and antagonists (MRS25...

Targeting the Incretin/Glucagon System with Triagonists to Treat Diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of GLP-1R-directed strategies is sub-maximal, and the only potent, sustainable treatment for metabolic dysfunction is bariatric surgery, necessitating the development of novel therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development o...

In Vivo Effects of μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Peptidomimetics Following Acute and Repeated Administration.

Mu opioid receptor (μ-receptor) agonists are used for pain management, but produce adverse effects including tolerance, dependence, and euphoria. The co-administration of a μ-receptor agonist with a delta opioid receptor (δ-receptor) antagonist has been shown to produce antinociception with reduced development of some side effects. We characterized the effects of three μ-receptor agonist/δ-receptor antagonist peptidomimetics in vivo after acute and repeated administration to determine if this profile p...

Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease.

Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for...

Structure-activity relationship studies and pharmacological characterization of N-heteroarylalkyl-substituted-2-(2-furanyl)thiazolo5,4-dpyrimidine-5,7-diamine-based derivatives as inverse agonists at human A adenosine receptor.

This paper describes the synthesis and characterization of N-(hetero)arylalkyl-substituted-thiazolo [5,4-d]pyrimidine-5,7-diamine derivatives (4-19) as novel human (h) A adenosine receptor (AR) inverse agonists. Competition binding and cyclic AMP assays indicate that the examined compounds behave as hA AR inverse agonists showing binding affinity values in the nanomolar or subnanomolar range. Notably, compounds 4, 5, 6 and 11 showed two affinity values for the hA ARs with the highest (KH) falling in the fem...

PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy.

We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of non-small cell lung cancer (NSCLC). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates phosphatase and tensin homolog (PTEN) to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to resistance to EGFR TK...

Pharmacokinetics and pharmacodynamics of intravesical and intravenous TMX-101 and TMX-202 in a F344 rat model.

To evaluate and compare the pharmacokinetic and pharmacodynamic properties of 2 investigational Toll-like receptor 7 agonists, TMX-101, and TMX-202 after intravenous and intravesical administration in a rat model. TLR-7 agonists are successfully used as topical treatment for various (pre)malignant skin lesions and are now under investigation as intravesical therapy for non-muscle-invasive bladder cancer.

Incretins: Beyond type 2 diabetes.

While the use of incretins, including GLP-1 receptor agonists and PDD-IV inhibitors, is well established in the treatment of type 2 diabetes, many other aspects of these agents are yet to be discovered and utilized for their potential clinical benefit. These include the potential role of GLP-1 receptor agonists in the induction of weight loss, blood pressure reduction, anti-inflammatory and nephro- and cardio-protective actions. Their potential benefit in type 1 diabetes is also being investigated. This rev...

β2-Adrenoceptor signalling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases.

Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the ...

Validation of a customized bioinformatics pipeline for a clinical next-generation sequencing test targeting solid tumor-associated variants.

Bioinformatic analysis is an integral and critical part of clinical next-generation sequencing. It is especially challenging for some pipelines to consistently identify insertions and deletions. We present the validation of an open source tumor amplicon pipeline (OTA-pipeline) for clinical next-generation sequencing targeting solid tumor-associated variants. Raw data generated from 557 TruSight Tumor 26 samples as well as in silico data were analyzed by the OTA-pipeline and legacy pipeline and compared. Dis...

Clinical Efficacy of Once-weekly Glucagonlike Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated for restoring normoglycemia in patients with type 2 diabetes (T2D). This review analyzed and compared the efficacy results from 30 trials with the once-weekly (OW) GLP-1 RAs albiglutide, dulaglutide, exenatide extended-release (ER) and semaglutide. The 4 OW GLP-1 RAs showed a higher reduction in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight, when compared to placebo. Semaglutide significantly reduced the HbA1c le...

Health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists are often recommended as part of combination therapy for type 2 diabetes when oral medication does not result in sufficient glycemic control. Several GLP-1 receptor agonists are available as weekly injections. These medications vary in their injection delivery systems, and these differences could impact quality of life and treatment preference. The purpose of this study was to estimate utilities associated with attributes of injection delivery systems for we...

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