Nerves: nootropics and compounds | sci-wiki

7,8,3'-Trihydroxyflavone

7,8,3'-Trihydroxyflavone is a close relative of 7,8-dihydroxyflavone with one extra hydroxyl, reported in the founding work on that compound to produce an even stronger effect on TrkB signalling. ⚠️ It has no measured binding affinity at TrkB. No Ki, Kd, IC50 or EC50 from a binding assay has ever been published for it, and the potency figures that circulate are fold-changes in signalling readouts, which are not measurements of target engagement. ⚠️ It was one of the compounds tested directly in an independent replication attempt, and it was inactive.

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Neuroprotection

ATH-1105

ATH-1105 is an oral small molecule being developed for ALS, from the same company as fosgonimeton and on the same claimed mechanism of positive modulation of the hepatocyte growth factor system. It has completed a phase 1 and has the strongest target-validation evidence anyone in this chemical programme has produced. ⚠️ It is not, despite frequent description, an oral version of fosgonimeton. The published structure is a different chemical class entirely, and neither of its two papers mentions fosgonimeton or dihexa. The two compounds share a claimed mechanism, not a scaffold.

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Nootropic

Deoxygedunin

Deoxygedunin is a natural product from the Indian neem tree and from andiroba seed oil, a limonoid of the gedunin family. It is sold alongside the flavone TrkB compounds and is chemically unrelated to them; it appears in that group only because it came out of the same screen. ⚠️ Its literature is remarkably small. PubMed indexes six papers containing the word at all, one of which merely identifies it as a constituent of seed oil and has nothing to do with the nervous system. There is no second independent pharmacology programme anywhere.

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Neuroprotection

Gambogic amide

Gambogic amide is a derivative of gambogic acid, a caged xanthone from the resin of a Southeast Asian tree, reported as a selective agonist of TrkA, the nerve growth factor receptor. ⚠️ The problem with that claim is inside its own discovery paper. The binding site it describes is intracellular, on the part of the receptor inside the cell, which is not how an extracellular signalling molecule activates a receptor tyrosine kinase. ⚠️ An independent group later measured cytotoxicity at concentrations overlapping the ones used to call it an agonist, and showed that toxicity does not go through TrkA at all.

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Neuroprotection

LM22B-10

LM22B-10 is a small molecule reported to activate both TrkB and TrkC, the receptors for BDNF and neurotrophin-3, from the same laboratory that produced LM22A-4. ⚠️ Two things about it deserve to come first. Chemically it is a triarylmethane, the same architecture as the leuco forms of malachite green and crystal violet, a class notorious for promiscuous and assay-interfering behaviour. And in recent literature the compound is used almost entirely as a generic activator of ERK signalling in non-neuronal cells, with no mention of TrkB or TrkC at all.

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Nootropic

R13

R13 is a prodrug of 7,8-dihydroxyflavone, built by capping both of the parent compound's hydroxyl groups with carbamate esters so it survives the gut better. It was the one candidate out of twenty screened derivatives that made it through to animal work. It roughly doubles oral bioavailability and half-life compared with the parent, and in Alzheimer's model mice it reduced amyloid deposition, protected synapses and improved maze performance. ⚠️ Its mechanism inherits an argument. R13 is assumed to work by releasing 7,8-dihydroxyflavone, which is assumed to activate the TrkB receptor, and that second assumption is contested, with independent groups having failed to reproduce receptor activation.

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