CNS-selective 5-HT4 partial agonist, designed as a brain-penetrant successor to Prucalopride. Prucalopride was validated in healthy people across three independent tasks: RAVLT (verbal recall), PILT (probabilistic learning), and emotional memory recognition, all showing significant improvement (Murphy et al., 2020). The problem was diarrhea from peripheral cAMP activity. Usmarapride fixes this with selective CNS penetration.
Mechanism: 5-HT4 agonism drives hippocampal cAMP, which triggers BDNF release, dendritic growth, and neurogenesis. Also reduces hippocampal excitability and blocks depotentiation, raising the LTP encoding threshold while protecting established traces. The pro-cognitive effect is hippocampus-specific: Prucalopride showed no effect on working memory or implicit contextual learning, which are PFC-dependent tasks (Murphy et al., 2020). For full cognitive coverage pair with Tropisetron, Neboglamine, an M1 ligand, or TAK-653.
The hippocampal excitability reduction is the anxiolytic mechanism. Hippocampal neurogenesis accounts for the antidepressant effects.
The standout synergy: Usmarapride drives hippocampal BDNF release, ACD-856 sensitizes TrkB for it. Mechanistically tight and subjectively strong.
Phase 1 class-level data from SUVN-D4010 (same 5-HT4 agonist class): generally safe, with relatively high headache occurrence above 15mg (Nirogi et al., 2021). Hard ceiling there.
Dose: 10mg (headaches above 15mg, hard ceiling (Nirogi et al., 2021)) Cycling: Daily Stacks: ACD-856 (Usmarapride releases BDNF, ACD-856 amplifies it at TrkB, strong mechanistic synergy), Tropisetron (5-HT3 antagonist + 5-HT4 agonist pairing) Notes: Phase 1 complete (Nirogi et al., 2021). Effects are hippocampus-specific, complement with PFC-targeting compounds for full coverage.
Bibliography
- Murphy, S. E., Wright, L. C., Browning, M., Cowen, P. J., & Harmer, C. J. (2020). A Role for 5-HT4 Receptors in Human Learning and Memory. Psychological Medicine, 50(16), 2722–2730. https://doi.org/10.1017/S0033291719002836
- Nirogi, R., Bhyrapuneni, G., Muddana, N. R., Goyal, V. K., Pandey, S. K., Mohammed, A. R., Ravula, J., Jetta, S., & Palacharla, V. R. C. (2021). First-in-Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5-HT4 Partial Agonist, SUVN-D4010, in Healthy Adult and Elderly Subjects. Clinical Drug Investigation, 41(5), 469–482. https://doi.org/10.1007/s40261-021-01027-4