Deoxygedunin, or 14,15-deoxygedunin, is a

tetranortriterpenoid The tetranortriterpenoid class of chemical compounds most noted for the chemical azadirachtin, extracted from the neem tree (''Azadirachta indica'') that displays insecticidal properties. Azadirachtin mimics insect hormones called ecdysones that re ...

isolated from the '' Indian neem tree'' a plant that has been in

traditional Indian medicine Indian medicine may refer to: *Ayurveda *Healthcare in India *Medical tourism in India *Pharmaceutical industry in India *Siddha medicine *Unani medicine *Native American ethnobotany *Medical ethnobotany of India See also *Traditional Tibetan medic ...

since ancient times as a remedy for various ailments.

Pharmacology

Deoxygedunin has been found to act as a potent, selective,

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

TrkB 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. TrkB is a recepto ...

, the main receptor of

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

(BDNF). It produces TrkB-dependent

neurotrophic Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...

and

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

effects in mice and enhances learning processes. In addition, deoxygedunin evokes rapid TrkB-dependent

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...

-like effects in the

forced swim test The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the ...

, an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

of depression, similarly to 7,8-dihydroxyflavone (7,8-DHF) and

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

, and notably with a greater potency than 7,8-DHF. The compound was discovered by the same group that identified 7,8-DHF and N-acetylserotonin as TrkB agonists.

Research

With

intraperitoneal injection Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...

to mice, deoxygedunin crosses the blood-brain-barrier into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and possesses a long duration of action, with onset of action at 2 hours post-administration and peaking between 4–8 hours. Relative to 7,8-DHF, deoxygedunin has weaker binding

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Part ...

for TrkB (K_d = 1.4 μM). However, it is more potent than 7,8-DHF ''in vivo'' with

in multiple assays. Deoxygedunin has also been found to be

orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

and

topically A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

active. The compound, in contrast to 7,8-DHF, has poor

water solubility An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be re ...

, and hence its

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. ...

, especially oral, may be suboptimal. The researchers who discovered deoxygedunin expressed that they were attempting to find analogues with improved water solubility that retained the biological activity of deoxygedunin, but, as of 2016, there appear to have been no subsequent reports on this effort since the original paper (2010) was published. They also stated in the paper that 7,8-DHF has a simpler

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of a ...

and that the

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

s were easier to modify for improved biological effects than the

gedunin Gedunin is a pentacyclic triterpenoid with the molecular formula C28H43O7. It is most notably found in Azadirachta indica, but is a constituent of several other plants. Gedunin shows therapeutic potential in the treatment of leukemia, and Parkins ...

s. Similarly to

, a closely structurally related compound also found in ''Azadirachta indica'', deoxygedunin has additionally been found to activate

HSF1 Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the ''HSF1'' gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regul ...

and induce

Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...

, and was observed to possess

effects in a model of

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

References

{{Growth factor receptor modulators Acetate esters Antidepressants 3-Furyl compounds Neuroprotective agents Nootropics Triterpenes TrkB agonists