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R13 (drug)

Index R13 (drug)

R13 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the potential treatment of Alzheimer's disease. [1]

24 relations: Agonist, Alzheimer's disease, Binding selectivity, Bioavailability, Biotransformation, Brain-derived neurotrophic factor, Flavonoid, Hydrolysis, List of investigational antidepressants, Liver, Microsome, Molecular modification, Mouth, Neurotrophin, Oral administration, Pharmacodynamics, Pharmacokinetics, Potency (pharmacology), Prodrug, R7 (drug), Receptor (biochemistry), Small molecule, Tropomyosin receptor kinase B, 7,8-Dihydroxyflavone.

Agonist

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response.

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Alzheimer's disease

Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and worsens over time.

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Binding selectivity

Binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex.

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Bioavailability

In pharmacology, bioavailability (BA or F) is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs.

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Biotransformation

Biotransformation is the chemical modification (or modifications) made by an organism on a chemical compound.

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Brain-derived neurotrophic factor

Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene.

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Flavonoid

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their color in nature) are a class of plant and fungus secondary metabolites.

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Hydrolysis

Hydrolysis is a term used for both an electro-chemical process and a biological one.

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List of investigational antidepressants

This is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved.

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Liver

The liver, an organ only found in vertebrates, detoxifies various metabolites, synthesizes proteins, and produces biochemicals necessary for digestion.

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Microsome

In cell biology, microsomes are vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, living cells.

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Molecular modification

Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug.

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Mouth

In animal anatomy, the mouth, also known as the oral cavity, buccal cavity, or in Latin cavum oris, is the opening through which many animals take in food and issue vocal sounds.

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Neurotrophin

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

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Oral administration

| name.

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Pharmacodynamics

Pharmacodynamics is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs).

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Pharmacokinetics

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism.

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Potency (pharmacology)

In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.

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Prodrug

A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug.

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R7 (drug)

R7 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the treatment of Alzheimer's disease. It is a structural modification and prodrug of 7,8-dihydroxyflavone (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. R7 was synthesized by the same researchers who were involved in the discovery of 7,8-DHF. A patent was filed for R7 in 2013 and was published in 2015. In 2016, it was reported to be in the preclinical stage of development. R7 was superseded by R13 because while R7 had a good drug profile in animals, it showed almost no conversion into 7,8-DHF in human liver microsomes. In 2010, 7,8-DHF, a naturally occurring flavonoid, was found to act as an agonist of the TrkB with nanomolar affinity (Kd ≈ 320 nM). Subsequently, 7,8-DHF demonstrated robust efficacy in animal models of Alzheimer's disease and a variety of other conditions, making it a highly promising potential therapeutic agent. Unfortunately, due to the presence of a vulnerable catechol group on its 2-phenyl-4H-chromene ring, 7,8-DHF is extensively conjugated via glucuronidation, sulfation, and methylation during first-pass metabolism in the liver and has a poor oral bioavailability of only 5% in mice upon oral administration. As such, 7,8-DHF itself is a poor candidate for clinical development as an oral medication. R7 is a derivative of 7,8-DHF with carbamate moieties on its hydroxyl groups, thereby protecting it from metabolism. As R7 is a slightly larger molecule than 7,8-DHF, 72.5 mg R7 is molecularly equivalent to 50 mg 7,8-DHF. Relative to a roughly molecularly equivalent dose of 7,8-DHF, the area-under-curve levels of R7 were found to be 7.2-fold higher upon oral administration to mice, and R7 hence has a greatly improved oral bioavailability in mice of approximately 35%. Moreover, whereas 7,8-DHF itself is mostly metabolized in mice within 30 minutes, 7,8-DHF was still detectable in plasma at 8 hours after administration with R7, indicating that R7 sustainably releases 7,8-DHF into circulation. In accordance, the terminal half-life of R7 is about 195 minutes (3.25 hours) in mice. The Tmax of R7 is about 60 minutes in mice, and its Cmax for a 78 mg/kg dose was 262 ng/mL, whereas that for a 50 mg/kg dose of 7,8-DHF was 70 ng/mL. Like 7,8-DHF, administration of R7 has been found to activate the TrkB in vivo in the mouse brain. Moreover, R7 was found to potently activate the TrkB and the downstream Akt signaling pathway upon oral administration, an action that was tightly correlated with plasma concentrations of 7,8-DHF. As such, R7 has shown in vivo efficacy as an agonist of the TrkB, including central activity, similarly to 7,8-DHF.

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Receptor (biochemistry)

In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell.

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Small molecule

Within the fields of molecular biology and pharmacology, a small molecule is a low molecular weight (< 900 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm.

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Tropomyosin receptor kinase B

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene.

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7,8-Dihydroxyflavone

7,8-Dihydroxyflavone (7,8-DHF) is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves.

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C19H16N2O6, R-13 (drug).

References

[1] https://en.wikipedia.org/wiki/R13_(drug)

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