spec sheet9 rows
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.
- A fully resolved chemical identity
- Reported neurotrophic and neuroprotective activity in the original work
- Cytotoxic to endothelial cells at 127 to 174 nanomolar, overlapping the concentrations used for its neurotrophic claims
- Blocks blood vessel formation, by a route that does not involve the receptor it is said to act on
- Its parent compound is studied as an anticancer agent because it kills cells
Mechanism
The compound is the amide derivative of gambogic acid, a caged prenylated xanthone from gamboge resin. It was reported as a selective TrkA that binds the receptor, triggers its phosphorylation and drives the downstream survival pathways, without acting on or TrkC [1].
⚠️ The binding site reported in that work is on the cytoplasmic juxtamembrane domain, meaning inside the cell. That is a serious internal problem rather than a detail. Receptor tyrosine kinases of this family are activated when a outside the cell cross-links two receptor molecules so their intracellular parts can phosphorylate each other. A molecule binding the intracellular face is not positioned to do that, and the paper does not reconcile the mechanism it proposes with the site it identifies.
⚠️ An independent group measured what else the compound does at similar concentrations. It suppressed VEGF and VEGFR2 signalling and inhibited blood vessel formation, killing endothelial cells with half-maximal concentrations of about 127 and 174 nanomolar, and showed explicitly that this activity is TrkA-independent [2]. Those concentrations sit inside the range used to demonstrate its neurotrophic effects, so at any dose said to protect neurons the molecule is also doing something cytotoxic by an unrelated route.
⚠️ Context from the chemistry: gambogic acid, its parent, is a well-known broadly cytotoxic natural product studied mainly as an anticancer agent. A neurotrophic claim for a close derivative of a cytotoxin deserves more confirmation than it has received.
⚠️ The whole class this belongs to rests on a contested claim. Nearly all the positive primary data for direct activation of by small molecules comes from one research group, and at least three independent teams have failed to reproduce receptor-level activation. Two of those were industrial drug-discovery groups using quantitative assays with a monoclonal antibody as a positive control [3][4], and a later review reached the same conclusion [5]. Downstream biological effects are often reproducible; the step in dispute is whether they happen by binding the receptor.
receptor fingerprint
VEGFR2 signalling and endothelial cellsSuppresses; cytotoxic
TrkA (NTRK1) receptorClaimed selective agonist; site is intracellular
Evidencehow good the literature is
One discovery paper making the neurotrophic claim, and independent work pointing the other way.
The 2007 paper reports selective TrkA agonism, receptor phosphorylation, downstream signalling and prevention of neuronal death [1].
⚠️ The 2021 independent study measured anti-angiogenic and cytotoxic activity in endothelial cells at 127 and 174 nanomolar and established that it is TrkA-independent [2]. There is no formal reevaluation paper for this compound of the kind published for the TrkB class; the sceptical case rests on the internal inconsistency of the original claim and on this measurement.
⚠️ No ChEMBL record exists for it, no trial has been registered, and there is no human data of any kind.
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
No human exposure and no toxicology in the context it is sold for.
⚠️ The relevant safety fact is that the compound is measurably cytotoxic at low nanomolar concentrations in endothelial cells and blocks blood vessel formation, by a route that does not involve the receptor it is meant to act on [2]. Whatever else that means, it is not the profile of an inert neurotrophic agent, and it overlaps the concentrations at which the neurotrophic claims are made.
Its parent compound is investigated as an anticancer agent precisely because it kills cells.
History
The compound came out of a mid-2000s screen for small molecules that could substitute for nerve growth factor, in the same laboratory tradition that produced the flavone TrkB candidates. It has since been taken up more by cancer and angiogenesis researchers than by neuroscientists, which is consistent with what the independent measurements show it does.
Resources
This entry is here for reference.
Research
- 2007first citedGambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activi…
- 2021most recentDo Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Publis…
- 1.Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death
- 2.Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner
- 3.A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease
- 4.Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists
- 5.Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists.
5 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is wrong with the binding site?
Receptors of this family switch on when something outside the cell binds two of them together, so their inner portions can activate each other. The site reported for this compound is on the inner portion, inside the cell. A molecule binding there is not in a position to bring two receptors together, so the proposed site and the proposed action do not fit, and the original paper does not resolve that.
Is the cytotoxicity a real concern?
It is measured, independent, and at concentrations that overlap the ones used to claim benefit. An outside group found it kills endothelial cells with half-maximal effects around 127 to 174 nanomolar and blocks blood vessel formation, and showed this happens without the receptor it is supposed to work through. That means any exposure said to protect neurons is also doing something else entirely.
Limitations of the evidence
- The binding site reported in its own discovery paper is intracellular, which does not fit the activation mechanism it claims
- Its cytotoxicity is explicitly TrkA-independent and overlaps its supposed working range
- No ChEMBL record, no registered trial and no human data
- No independent confirmation of the neurotrophic claim
- Belongs to a class of small-molecule neurotrophin mimics whose receptor-level claims failed replication
Adverse effects
- Cytotoxic to endothelial cells at 127 to 174 nanomolar, overlapping the concentrations used for its neurotrophic claims
- Blocks blood vessel formation, by a route that does not involve the receptor it is said to act on
- Its parent compound is studied as an anticancer agent because it kills cells