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.
Dose: 10-30µg (microdose) Cycling: off-season, daily during restore phase alongside Cerebrolysin Stacks: Cerebrolysin (structural dendritic repair), ACD-856 (M1 + TrkB convergence on memory consolidation) Notes: Phase 1 complete; Phase 2 ongoing. Don’t overlap with the active-season glutamate stack, uncharacterized interaction. Racemic product; AF710A is inert at these doses.
Bibliography
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