Cholinergic Cognition: Tropisetron & AF710B
Research and education, not medical advice.
Now satisfied with my dopamine research, I’m taking on other challenges such as increasing human IQ. Two of the strongest routes I’ve found run through the cholinergic system: the α7 nicotinic receptor, targeted by Tropisetron, and the M1 muscarinic receptor, targeted by AF710B. M1 muscarinic receptors are one of the few targets evidenced to enhance cognition in healthy people. Both of these compounds fit every criteria required to earn the title “nootropic,” and both may be among the most effective in existence.
Tropisetron
This led me to discover Tropisetron, a superior α7 nicotinic receptor partial agonist and also 5-HT3 antagonist.
Mechanism: α7 nicotinic receptor partial agonist
So I was very much excited reading this study, where GTS-21 improved working memory, episodic memory and attention. Not only was this conducted in healthy people, but these domains of cognition are important to IQ, consciousness and executive function, respectively. GTS-21 is a failure, and I’ll explain why. But it’s a selective α7 nicotinic receptor partial agonist, so we can learn a lot from it.
Before progressing, I would like to outline the discrepancies between nicotine and α7 nicotinic receptors.
Addiction: This is people’s first thought when they hear “nicotinic”. But nicotine is not a selective α7 agonist, and in fact it has more bias towards α4. This is what causes dopamine release, and therefore euphoria and addiction. [6] [10]
Cognition: Unsurprisingly, short-term cognitive benefits of nicotine are likely mediated by α7 nicotinic receptors. This is bolstered by Wellbutrin (Bupropion) not impairing cognition in healthy people. [11] Compared to other nicotinic receptors, its affinity for α7 is the lowest. [12]
Tolerance & Withdrawal: Tolerance at the nicotinic receptors is atypical and occurs through multiple mechanisms. In nicotine’s case, α4 upregulation on inhibitory GABAergic neurons contributes to this, as well as the reduced dopamine release during withdrawal. [10] But with α7s, it would appear it a structural issue of ligands themselves, with some remaining bound long beyond their half life and “trapping” the receptor in a desensitized state. [7] This, along with nausea is what caused GTS-21 to fail. [4] But this doesn’t appear to be the case with Tropisetron, which could be due structural dissimilarity, or perhaps it acting as a co-agonist and “priming” the receptor for activation, which is why increasing acetylcholine enhances its nootropic effects. [2] Aside from the fact that Tropisetron is quite literally an anti-nausea medicine with a long history of prescription use.
Both actions appear sustainable in animal and human models which is extremely good news for a nicotinic drug, as many others are well known to have issues with consistency. While it isn’t working some voodoo magic like Bromantane, when it comes to selective benefits, this is about the best you could hope for.
Other: α7 nicotinic receptor partial agonists appear to be better anti-inflammatory agents than nicotine. [9]
Cognition and the 5-HT3 side
In the medical world, treating illness is priority. As such, studies in the healthy are uncommon. However, Tropisetron has improved cognition in conditions characterized by learning disorders, such as Schizophrenia. [3] Nootropic effects are also shown in primates [2] correlating with the results found in healthy people given GTS-21.
It is a very broadly applicable drug, showing promise for OCD, [23] and Fibromyalgia. Also anxiety, but only mildly. [16] It reports strong antidepressant effects in rodent models, [15] which correlates with other 5-HT3 antagonists. [21] 5-HT3 antagonism is a desirable target, as it isn’t associated with side effects or tolerance [13] and appears neuroprotective [20] and pro-cognitive [17] [18] [19] potentially due to enhancing acetylcholine release. An atypical SSRI and 5-HT3 antagonist, Vortioxetine [14] was also shown to improve cognition in the majorly depressed, an unexpected outcome for most antidepressants.
Really it doesn’t make sense to have a selective drug with no 5-HT3 antagonism due to extreme nausea.
Neuroprotection, Alzheimer’s and excitotoxicity
α7 nicotinic receptor overactivation can cause excitotoxicity. But a partial agonist is neuroprotective, dampening excitotoxic potential while stimulating calcium influx in a way that promotes cognition. But Tropisetron is also valuable for Alzheimer’s (AD), binding to beta amyloids and improving memory better than current AD treatments such as Donepezil and Memantine. [25] It is a 5-HT3 antagonist, but this doesn’t appear responsible for all of its neuroprotective effects. Improved blood flow from α7 partial agonism appears to play a role. [26]
In primates, it is shown that Donepezil, an acetylcholinesterase inhibitor, significantly potentiates the working memory enhancement of Tropisetron, likely by increasing acetylcholine that would bind to α7. And interestingly, Tropisetron improved memory in an Alzheimer’s model in mice better than both Donepezil and Memantine.
On Memantine specifically: both NMDA antagonism and a7 antagonism reduce excitototixicty which is why they help neurodegenerative disorders like Alzheimer’s. But make no mistake, this impairs cognition. How memantine got looped in with nootropics I have no clue. I think that Wellbutrin not impairing cognition in healthy people does actually support what I’m saying.
Working memory benefits downstream of α7 are potentially mediated by D-Serine release, further substantiating the role of D-Serine modulators as nootropics. See Raising IQ: AMPA PAMs, NMDA & D-Serine.
Other: Tropisetron shows promise for lifespan extension and healthy aging with antioxidant and anti-inflammatory effects, [22] has data to suggest it benefits fatty liver disease [24] and although it was GTS-21 to be trialed, potentially ADHD.
Dosing, ROA and shelf life
Tropisetron is mildly dopaminergic at low doses (<10mg), and antidopaminergic at high doses (>10mg). [8] If you actually read the study you will see that dopamine is decreased after 10mg+ and increased by <5mg. See Dopamine.
Route of administration: Oral. Tropisetron is best used orally at 5-10mg. It has a half life of 6 hours but effects that may persist for much longer. Shelf life is around 3 years. A solution with 20mg/mL is available. The pipet is labeled, so the concentration is accurate every time.
At 10mg+ you may get constipation, this happened in about 12% of people.
Stacking, and my stack
Similarly to Piracetam, it would appear increased acetylcholine improves its memory enhancement. ALCAR, an endogenous and potent cholinergic seems logical here. Tropisetron’s antidepressant effects are potentiated by increased cAMP, so Bromantane or PDEIs such as caffeine would make sense.
Definitely it depends on what your exact goals are. For instance I think a more selective action at a7 is going to be more desirable overall but if you’re cramming some information in for a test or something then enhancing it with more acetylcholine is going to come as a major benefit.
My stack is Tropisetron 10mg + Bromantane 2 sprays + white willow bark extract + ALCAR + a few cups of coffee. Sometimes I take other things like a multivitamin, Hesperidin, DL-Serine and more. Every once in a while Pemoline.
It feels like it has antidepressant effects. I feel like I can use my motivation to do more productive tasks. And I feel less anxious. I take it for high blood pressure when I’m drinking multiple cups of coffee.
On agmatine, for the record: I’ve never claimed agmatine sulfate is any insane nootropic. It was good for my depression when I had it, and that’s about it. As for D-Serine, the NMDA glycine site (or D-Serine site) is one of the most important sites. But it can be done so much better. As for Tropisetron, this is something that is harder to improve. I think it serves a place long term and is most worthwhile.
Summary
Tropisetron fits every criteria required to earn the title “nootropic”. Furthermore, it may be one of the most effective in existence due to its selective actions at α7 nicotinic receptors and 5-HT3. Tropisetron encompasses a wide range of potential benefits, from improving cognitive function to generalized benefits to mental health.
AF710B
In this post I hope to discuss M1 ligands, but more specifically why they are effective cognitive enhancers, and ultimately why I chose AF710B to list on Everychem. A long anticipated nootropic agent, as it targets both Sigma1 and M1 simultaneously and in addition to its neuroprotective effects, has real potential to be one of the most effective nootropics to date.
M1 ligands as potent cognitive enhancers
M1 muscarinic receptors are one of the few targets evidenced to enhance cognition in healthy people. VU319 demonstrated this in one clinical trial, where it profoundly improved selective attention in a continuous performance task (high effect size, d = 1.2), and additionally enhanced reaction speed. Reportedly, Incidental Memory Tests which measure passive long-term memory formation also correlated with EEG P300 amplitudes (high effect size, d = 0.8), which suggest a relationship between this drug and the enhanced formation of long term memory. [1]
Another drug, partial agonist of M1 receptors HTL0018318, also improved working memory and short term learning in healthy young and old people with moderate to high effect sizes, which is important given the distinction of these findings in how they relate to IQ. [2]
TAK-071 is a selective M1 PAM, but unlike the other two drugs, hasn’t been tested in healthy people for cognition. However, it was tested in Parkinson’s patients with cognitive impairment, wherein it improved executive function, episodic memory and attention. It did not improve cognitive load which is most relevant to Parkinson’s, which indicated lack of efficacy for this drug in Parkinson’s. [3]
How M1 works, and AF710B’s M1/Sigma1 mechanism
These findings can be partially explained by M1’s role in the dorsolateral prefrontal cortex (DLPFC), where its activity follows an inverted-U response upon being activated, wherein above and below a certain threshold it can improve working memory in primates, through modulating the activity of delay cells in the DLPFC. This is because M1 increases calcium-CAMP signaling, which then opens KCNQ channels. [4]
AF710B is very selective over off-targets, but diverges through its distinct binding at the M1-Sigma1 complex, therefore acting as a dual allosteric agonist of M1 and agonist at Sigma1, manifesting its allosterism of M1 at a much lower dose than its agonist profile. [6] This mixed signaling gave AF710B a unique advantage in an Alzheimer’s model over selective ligands at M1 and Sigma1, leading to it being chosen over them to progress through clinical trials.
The nature of this receptor complex is a topic of active investigation, however it’s demonstrated that it can more selectively lower the threshold of ERK-driven LTP by acetylcholine by a magnitude of 1500%, while the mechanics for LTD are left relatively the same. [5] Thus regional neuroplasticity and new memory formation is greatly enhanced with this compound, but its specificity to LTP-driven activity is much more focused in contrast to other M1 PAMs.
Sigma1 has been widely speculated to be a procognitive target, but data in healthy subjects given a ligand selectively binding it is lacking. Though, it’s commonly understood that as a chaperone receptor it can modulate the effects of other receptors, like in this case with M1. Notably, blockade of Sigma1 diminished the memory restorative effects of AF710B in impaired rodents.
The data: supraphysiological cognition
What this means for its cognitive profile in healthy people is yet to be established, though in healthy rodents it improved novel object recognition (NOR) memory in a modified test representing working memory, and escape latency representing spatial learning and memory. These findings are in line with what has previously been demonstrated to occur in people with heightened M1 activity. NOR scores in Alzheimer’s-modeled rodents given AF710B were above that of healthy rodents given nothing, indicating a supraphysiological effect of this drug, and this may indicate LTP-orientation in the aforementioned human studies. [6]
Impaired rodents additionally show sustained benefits even five weeks after cessation. [5]
Safety, and clinical trials: AF710B has completed its Phase 1 clinical trial, where it was deemed safe and tolerable under high dose escalation. It is currently undergoing Phase 2 clinical trials for Schizophrenia and is planned to enter trials for Alzheimer’s, however it seems as though M1 would make an excellent candidate for the treatment of ADHD given the highly replicable attention enhancement and high effect size seen in multiple pieces of literature. [7]
Why I listed it, and Everychem’s racemic listing
Following the trajectory now on multiple projects, it seemed fitting to look at positive allosteric modulators at M1, given the relatively positive reception of previous allosteric ligands at critical cognitive targets such as TAK-653, Neboglamine, and recently ACD856. TAK-071 and VU319 had unreasonably high dose requirements and complex synthesis routes which led to disqualification as Everychem listings. Further, creating selective ligands at M1 posed a challenge for pharmaceutical companies due to the high co-expression of this receptor with unwanted off-targets, such as M2 and M5. It seemed like we had parsed through every M1 PAM with phase 1 clinical trials or above until our discovery of AF710B.
Everychem’s listing is racemic, whereas AF710B is enantioselective. This means that it is 50:50 AF710B, and biologically inactive AF710A which has negligible, if any binding at the doses used. This was done to make the project feasible, as enantiomer separation would increase the cost of production much more than double.
Write a comment