AF710B

Dual allosteric agonist at the M1-Sigma-1 receptor complex (Hall et al., 2018). M1 agonism feeds into calcium-cAMP, which gates KCNQ channels and modulates DLPFC delay-cell firing in an inverted-U pattern. The class-level human evidence is solid:

• VU319 produced d=1.2 on continuous performance task and correlated EEG P300 amplitudes (d=0.8) with long-term memory formation (Conley et al., 2020)
• HTL0018318 improved working memory and short-term learning with moderate-to-high effect sizes across young and old subjects (Bakker et al., 2021)
• TAK-071 adds further clinical validation (Shanbhag et al., 2025)
• AC-260584 extends the pattern to allosteric M1 agonism specifically (Bradley et al., 2010). Sigma-1 is a chaperone receptor modulating ERK signaling, ER stress response, and mitochondrial integrity (Hall et al., 2018)

the M1-Sigma-1 complex is what makes AF710B distinct from selective ligands at either target alone (Hall et al., 2018). The combined allosteric effect lowers the ERK-driven LTP threshold by 1500% via Acetylcholine, with LTD mechanics mostly unchanged, making it highly LTP-selective (Hall et al., 2018). NOR performance in Alzheimer’s-modeled rodents given AF710B exceeded that of untreated healthy controls, a supraphysiological enhancement (Hall et al., 2018). Benefits persist around 5 weeks post-cessation, indicating structural plasticity rather than receptor occupancy (Hall et al., 2018). Sigma-1 blockade diminishes these effects, confirming both axes are necessary (Hall et al., 2018).

Phase 1 complete; Phase 2 ongoing for schizophrenia, planned for Alzheimer’s. ADHD is an obvious under-investigated target given the attention enhancement effect sizes in the M1 literature.

Off-season role: Sigma-1 agonism directly repairs ER stress and mitochondrial dysfunction that accumulates during a high-glutamate active season, while M1 keeps memory circuits functional during the TAK-653 washout.

Everychem listing is racemic (50:50 AF710B active + AF710A biologically inactive), enantiomer separation would be prohibitively expensive.

anecdotally, i noticed a significant increase in work ethic. Read and annotated a whole paper at 6 am before any classes. my attention is exceptionally fragmented thanks to tilling window management but this got me to “stay still” for an hour straight

Bakker, C., Tasker, T., Liptrot, J., Hart, E. P., Klaassen, E. S., Doll, R. J., Brown, G. A., Brown, A., Congreve, M., Weir, M., Marshall, F. H., Cross, D. M., Groeneveld, G. J., & Nathan, P. J. (2021). Safety, Pharmacokinetics and Exploratory pro-Cognitive Effects of HTL0018318, a Selective M1 Receptor Agonist, in Healthy Younger Adult and Elderly Subjects: A Multiple Ascending Dose Study. Alzheimer’s Research & Therapy, 13(1), 87. https://doi.org/10.1186/s13195-021-00816-5

Bradley, S. R., Lameh, J., Ohrmund, L., Son, T., Bajpai, A., Nguyen, D., Friberg, M., Burstein, E. S., Spalding, T. A., Ott, T. R., Schiffer, H. H., Tabatabaei, A., McFarland, K., Davis, R. E., & Bonhaus, D. W. (2010). AC-260584, an Orally Bioavailable M1 Muscarinic Receptor Allosteric Agonist, Improves Cognitive Performance in an Animal Model. Neuropharmacology, 58(2), 365–373. https://doi.org/10.1016/j.neuropharm.2009.10.003

Conley, A. C., Key, A. P., Blackford, J. U., Rook, J. M., Conn, J., Lindsley, C. W., Jones, C. K., & Newhouse, P. A. (2020). Cognitive Performance Effects Following a Single Dose of the M₁ Muscarinic Positive Allosteric Modulator VU319: Human/Human Trials: Cognitive Enhancement. Alzheimer’s & Dementia, 16(S9), e045339. https://doi.org/10.1002/alz.045339

Hall, H., Iulita, M. F., Gubert, P., Flores Aguilar, L., Ducatenzeiler, A., Fisher, A., & Cuello, A. C. (2018). AF710B, an M1/Sigma-1 Receptor Agonist with Long-lasting Disease-modifying Properties in a Transgenic Rat Model of Alzheimer’s Disease. Alzheimer’s & Dementia, 14(6), 811–823. https://doi.org/10.1016/j.jalz.2017.11.009

Shanbhag, N. M., Padmanabhan, J. L., Zhang, Z., Harel, B. T., Jia, H., Kangarloo, T., Yin, W., Dowling, A. V., Laurenza, A., Khudyakov, P., Galinsky, K., Latzman, R. D., Simuni, T., Weintraub, D., Horak, F. B., Lustig, C., Maruff, P., & Simen, A. A. (2025). An Acetylcholine M1 Receptor–Positive Allosteric Modulator (TAK-071) in Parkinson Disease With Cognitive Impairment: A Phase 2 Randomized Clinical Trial. JAMA Neurology, 82(2), 152–159. https://doi.org/10.1001/jamaneurol.2024.4519