PAM at the NMDA glycine/D-Serine binding site (Lanza & Makovec, 1997). D-Serine is released regionally during learning events; Neboglamine amplifies its binding at those moments, not continuously. Same design principle as TAK-653 being a better AMPA agent than agonists: allosteric bias makes enhancement context-dependent rather than constant.
The cascade: AMPA activation triggers delayed NMDA firing (NMDA currents rise as a delayed response to AMPA (Watt et al., 2004); AMPA trafficking is required for NMDA to function at all (Malinow & Malenka, 2002)), then Neboglamine amplifies NR2B binding at that NMDA step (Duffy et al., 2008). TAK-653 and Neboglamine hit sequential nodes in the same pathway, not the same point twice. The combination could push TAK’s ~7pt IQ effect considerably higher. Also reverses NMDA antagonist-induced cognitive impairment, as do AMPA PAMs (Ranganathan et al., 2017) and D-Serine (Karasawa et al., 2008).
More potent than D-Serine: ~50mg HED improves learning acquisition in healthy rats (Garofalo et al., 1996). D-Serine now thought to require >8g for cognitive effects, making Neboglamine a large practical improvement. One head-to-head comparison showed twice the NMDA activation potency (Lanza & Makovec, 1997) (dose discrepancy makes direct extrapolation rough, but the direction is clear). Glycine-site PAMs improve cognition in healthy young adults (Levin et al., 2015) and the elderly (Avellar et al., 2016).
Safer than D-Serine: D-Serine causes oxidative stress even at small amounts, not reversed by L-Serine in vitro (Da Silva et al., 2009). The indirect PAM mechanism avoids this entirely. Phase 1 demonstrated safety and tolerability; 200mg selected for maximum effects and demonstrated ischemia prevention at that dose.
Only drug with this mechanism.
Stacks well with TAK-653 (primary synergy, sequential AMPA→NMDA pathway nodes), ACD-856 (BDNF downstream of NMDA/NR2B activation)
Bibliography
- Avellar, M., Scoriels, L., Madeira, C., Vargas-Lopes, C., Marques, P., Dantas, C., Manhães, A. C., Leite, H., & Panizzutti, R. (2016). The Effect of D-serine Administration on Cognition and Mood in Older Adults. Oncotarget, 7(11), 11881–11888. https://doi.org/10.18632/oncotarget.7691
- Da Silva, L. D. B., Leipnitz, G., Seminotti, B., Fernandes, C. G., Beskow, A. P., Amaral, A. U., & Wajner, M. (2009). D-Serine Induces Lipid and Protein Oxidative Damage and Decreases Glutathione Levels in Brain Cortex of Rats. Brain Research, 1256, 34–42. https://doi.org/10.1016/j.brainres.2008.12.036
- Duffy, S., Labrie, V., & Roder, J. C. (2008). D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning. Neuropsychopharmacology, 33(5), 1004–1018. https://doi.org/10.1038/sj.npp.1301486
- Garofalo, P., Colombo, S., Lanza, M., Revel, L., & Makovec, F. (1996). CR 2249: A New Putative Memory Enhancer. Behavioural Studies on Learning and Memory in Rats and Mice. Journal of Pharmacy and Pharmacology, 48(12), 1290–1297. https://doi.org/10.1111/j.2042-7158.1996.tb03938.x
- Karasawa, J.-I., Hashimoto, K., & Chaki, S. (2008). D-Serine and a Glycine Transporter Inhibitor Improve MK-801-induced Cognitive Deficits in a Novel Object Recognition Test in Rats. Behavioural Brain Research, 186(1), 78–83. https://doi.org/10.1016/j.bbr.2007.07.033
- Lanza, M., & Makovec, F. (1997). Cognition Enhancing Profile of CR 2249, a New NMDA-Glycine Site Modulator. CNS Drug Reviews, 3(3), 245–259. https://doi.org/10.1111/j.1527-3458.1997.tb00326.x
- Levin, R., Dor-Abarbanel, A. E., Edelman, S., Durrant, A. R., Hashimoto, K., Javitt, D. C., & Heresco-Levy, U. (2015). Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor Co-Agonist D-serine in Healthy Humans: Initial Findings. Journal of Psychiatric Research, 61, 188–195. https://doi.org/10.1016/j.jpsychires.2014.12.007
- Malinow, R., & Malenka, R. C. (2002). AMPA Receptor Trafficking and Synaptic Plasticity. Annual Review of Neuroscience, 25(1), 103–126. https://doi.org/10.1146/annurev.neuro.25.112701.142758
- Ranganathan, M., DeMartinis, N., Huguenel, B., Gaudreault, F., Bednar, M. M., Shaffer, C. L., Gupta, S., Cahill, J., Sherif, M. A., Mancuso, J., Zumpano, L., & D’Souza, D. C. (2017). Attenuation of Ketamine-Induced Impairment in Verbal Learning and Memory in Healthy Volunteers by the AMPA Receptor Potentiator PF-04958242. Molecular Psychiatry, 22(11), 1633–1640. https://doi.org/10.1038/mp.2017.6
- Watt, A. J., Sjöström, P. J., Häusser, M., Nelson, S. B., & Turrigiano, G. G. (2004). A Proportional but Slower NMDA Potentiation Follows AMPA Potentiation in LTP. Nature Neuroscience, 7(5), 518–524. https://doi.org/10.1038/nn1220