ColuracetamvsPhenylpiracetam

Coluracetam's primary mechanism is enhancement of high-affinity choline uptake (HACU) in hippocampal neurons — the rate-limiting step in acetylcholine synthesis. HACU is mediated by the high-affinity choline transporter (CHT1/SLC5A7), which coluracetam upregulates or potentiates, increasing the Vmax of choline transport into presynaptic terminals. By making this process more efficient, coluracetam increases acetylcholine production and vesicular packaging via the vesicular acetylcholine transporter (VAChT) even when choline levels are normal. This enhances cholinergic transmission in the hippocampus, cortex, and retina — explaining reports of enhanced color vision and visual acuity. Coluracetam also has minor AMPA receptor positive allosteric modulation. The compound was studied for treatment-resistant depression, possibly through cholinergic modulation of mood circuits.

Phenylpiracetam modulates AMPA and NMDA glutamate receptors like other racetams through positive allosteric modulation. The phenyl group confers additional affinity for dopamine (DAT) and norepinephrine (NET) transporters, acting as a weak reuptake inhibitor and increasing synaptic catecholamine availability — providing stimulatory and motivational effects. It binds to α4β2 and α7 nicotinic acetylcholine receptors as a positive allosteric modulator, enhancing cholinergic transmission in the prefrontal cortex and hippocampus. The phenyl moiety improves blood-brain barrier penetration via increased lipophilicity and potentially P-glycoprotein substrate properties. Downstream effects include enhanced CREB phosphorylation and BDNF expression. The combination of glutamatergic, dopaminergic, noradrenergic, and cholinergic modulation produces synergistic cognitive enhancement.