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| Other names | 14,15-Deoxygedunin |
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| Formula | C28H34O6 |
| Molar mass | 466.574 g·mol−1 |
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Deoxygedunin, or 14,15-deoxygedunin, is a tetranortriterpenoid isolated from the Indian neem tree [1] [2] a plant that has been in traditional Indian medicine since ancient times as a remedy for various ailments. [3]
Deoxygedunin has been found to act as a potent, selective, small-molecule agonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). [1] [2] It produces TrkB-dependent neurotrophic and neuroprotective effects in mice and enhances learning processes. [1] [4] In addition, deoxygedunin evokes rapid TrkB-dependent antidepressant-like effects in the forced swim test, an animal model of depression, similarly to 7,8-dihydroxyflavone (7,8-DHF) and ketamine, and notably with a greater potency than 7,8-DHF. [1] [2] [5] The compound was discovered by the same group that identified 7,8-DHF and N-acetylserotonin as TrkB agonists. [1]
With intraperitoneal injection to mice, deoxygedunin crosses the blood-brain-barrier into the central nervous system and possesses a long duration of action, with onset of action at 2 hours post-administration and peaking between 4–8 hours. [1] Relative to 7,8-DHF, deoxygedunin has weaker binding affinity for TrkB (Kd = 1.4 μM). [1] [2] However, it is more potent than 7,8-DHF in vivo with intraperitoneal injection in multiple assays. [1] Deoxygedunin has also been found to be orally and topically active. [1] [4] The compound, in contrast to 7,8-DHF, has poor water solubility, [1] and hence its bioavailability, especially oral, may be suboptimal. [6] 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. [1] They also stated in the paper that 7,8-DHF has a simpler chemical structure and that the flavonoids were easier to modify for improved biological effects than the gedunins. [1]
Similarly to gedunin, a closely structurally related compound also found in Azadirachta indica, deoxygedunin has additionally been found to activate HSF1 and induce Hsp70, and was observed to possess neuroprotective effects in a model of Huntington's disease. [7]
Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.
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 receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.
N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.
SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors. It has been used to investigate the mechanism of action of caffeine, which is a mixed A1 / A2A antagonist, and has shown that the A2A receptor is primarily responsible for the stimulant and ergogenic effects of caffeine, but blockade of both A1 and A2A receptors is required to accurately replicate caffeine's effects in animals. SCH-58261 has also shown antidepressant, nootropic and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.
Diosmetin, also known as 5,7,3′-trihydroxy-4′-methoxyflavone, is an O-methylated flavone, a chemical compound that can be found in the Caucasian vetch.
Norwogonin, also known as 5,7,8-trihydroxyflavone (5,7,8-THF), is a flavone, a naturally occurring flavonoid-like chemical compound which is found in Scutellaria baicalensis. It has been found to act as an agonist of the TrkB, the main signaling receptor of brain-derived neurotrophic factor (BDNF), and appears to possess roughly the same activity in this regard to that of the closely related but more well-known tropoflavin (7,8-DHF).
Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13, is under development for the treatment of Alzheimer's disease.
Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.
Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as an anesthetic in comparison.
ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.
LM22A-4 is a synthetic, selective small-molecule partial agonist of TrkB (EC50 for TrkB activation = 200–500 pM; IC50 for inhibition of BDNF binding to TrkB = 47 nM; IA = ~85%), the main receptor of brain-derived neurotrophic factor. It has been found to possess poor blood-brain-barrier penetration when administered systemically, so LM22A-4 has been given to animals instead via intranasal administration, with central nervous system TrkB activation observed. The compound produces neurogenic and neuroprotective effects in animals, and shows beneficial effects on respiration in animal models of Rett syndrome.
Cyclotraxin B (CTX-B) is a small (1200 Da) cyclic peptide and highly potent, selective, non-competitive antagonist or negative allosteric modulator of TrkB (IC50 = 0.30 nM), the main receptor of brain-derived neurotrophic factor (BDNF), which itself was derived from BDNF. It crosses the blood-brain-barrier with systemic administration and produces anxiolytic-like effects in animals, though notably not antidepressant-like effects. The compound has also been found to produce analgesic effects in animal models of neuropathic pain. In addition to TrkB, CTX-B has been found to be an allosteric modulator of VEGFR2, one of the receptors of vascular endothelial growth factor (VEGF).
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 tropoflavin (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 tropoflavin. 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 tropoflavin in human liver microsomes.
7,8,3′-Trihydroxyflavone (7,8,3'-THF) is a flavone and small-molecule agonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF), that was derived from tropoflavin (7,8-DHF). Relative to tropoflavin, 7,8,3'-THF is 2–3-fold more potent in vitro as a TrkB agonist. 7,3’-Dihydroxyflavone (7,3'-DHF) is also more potent than tropoflavin in vitro, indicating that a 3'-hydroxy group on the B-ring enhances TrkB agonistic activity. 7,8,3'-THF has been tested in vivo and was found to produce TrkB-dependent neuroprotective effects in mice similarly to tropoflavin.
Eutropoflavin (4'-Dimethylamino-7,8-dihydroxyflavone) is a synthetic flavone and selective small-molecule agonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF), which was derived from structural modification of tropoflavin (7,8-DHF). Relative to tropoflavin, eutropoflavin possesses higher agonistic activity at TrkB, is significantly more potent than tropoflavin both in vitro and in vivo, and has a longer duration of action. The compound has been found to produce neuroprotective and neurogenic effects in the brain and spinal cord as well as antidepressant-like effects in animals.
BNN-20, also known as 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol, is a synthetic neurosteroid, "microneurotrophin", and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA). It acts as a selective, high-affinity, centrally active agonist of the TrkA, TrkB, and p75NTR, receptors for the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as for DHEA and DHEA sulfate (DHEA-S). The drug has been suggested as a potential novel treatment for Parkinson's disease and other conditions.
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. It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. The compound is a replacement for the earlier tropoflavin prodrug R7 and has similar properties to it. It was developed because while R7 displayed a good drug profile in animal studies, it showed almost no conversion into tropoflavin in human liver microsomes. In contrast to R7, R13 is readily hydrolyzed into tropoflavin in human liver microsomes.
Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors. Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.
