Tag: Dipeptide nootropic (proline-glycine N-phenyl)

Noopept (INN: omberacetam; development code GVS-111; N-phenylacetyl-L-prolylglycine ethyl ester; CAS 157115-85-0; molecular formula C17H22N2O4; molecular weight 318.37 g/mol) is a synthetic dipeptide nootropic and neuroprotectant developed in the mid-1990s at the V.V. Zakusov Research Institute of Pharmacology of the Russian Academy of Medical Sciences by Tatyana Gudasheva, Rita Ostrovskaya, and Sergei Seredenin using a drug-based peptide design strategy that models the pyrrolidone ring of piracetam as the central element of a beta-turn dipeptide. The compound is approved in the Russian Federation (registration 2006) and several former Soviet states for the treatment of cognitive impairment of vascular and post-traumatic origin at oral doses of 10 to 30 mg per day, doses approximately 1000-fold lower by mass than the effective doses of piracetam (1200 to 4800 mg per day), its structural prototype. Noopept is not approved by the United States Food and Drug Administration, the European Medicines Agency, or the regulatory authorities of Japan, Australia, or Canada. It is sold internationally as a research-grade compound and as an unregulated dietary supplement in several jurisdictions.

The pharmacological mechanism of noopept is multifactorial and operates through both the parent compound and its principal active metabolite, cycloprolylglycine (cyclo-L-prolylglycine, CPG), an endogenous brain dipeptide. The parent compound and CPG function as positive allosteric modulators of AMPA-subtype ionotropic glutamate receptors, increasing glutamate sensitivity without direct agonist binding. Noopept modulates NMDA receptor expression and function, upregulates the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in hippocampal and cortical neurons on chronic administration, activates the transcription factor hypoxia-inducible factor 1 (HIF-1) through inhibition of prolyl hydroxylase, and provides direct neuroprotection against amyloid-beta peptide toxicity, glutamate excitotoxicity, oxidative stress, and calcium overload in cellular and animal models. In Alzheimer’s disease cellular models, noopept attenuates tau hyperphosphorylation at Ser396 and reduces apoptosis through suppression of the mitochondrial apoptotic pathway.

Pharmacokinetics in humans are characterized by rapid oral absorption (time to peak plasma concentration approximately 15 to 20 minutes), extensive first-pass metabolism yielding an oral bioavailability of approximately 10 percent relative to parenteral administration, rapid hydrolysis of the parent ester to the active metabolite cycloprolylglycine, and a short plasma half-life of the parent compound. The pharmacological effect persists for 3 to 6 hours after oral dosing, substantially longer than the plasma residence of the parent compound, consistent with the contribution of the longer-lived CPG metabolite and downstream transcriptional effects on neurotrophic factor expression. The compound does not appear to undergo significant cytochrome P450-mediated metabolism; the principal biotransformation is peptidase-mediated ester hydrolysis and amide cleavage.

The clinical evidence base is concentrated in Russian-language literature and is modest by Western regulatory standards. The principal English-language clinical study is the Neznamov and Teleshova (2009) comparative trial of noopept (20 mg per day) and piracetam (1200 mg per day) in 53 patients with mild cognitive disorders of vascular and traumatic origin over 56 days, which demonstrated comparable cognitive improvement with a 1.8-fold lower incidence of adverse events in the noopept arm. Preclinical evidence is more extensive, spanning rodent models of ischemic brain injury, Alzheimer’s disease (both amyloid-beta infusion and transgenic models), traumatic brain injury, and age-related cognitive decline. The compound is well tolerated at recommended doses; the principal adverse events are sleep disturbance, irritability, and transient blood pressure elevation, all at low incidence. No serious adverse events have been reported in published clinical studies at doses up to 30 mg per day for periods up to 56 days. Long-term safety data beyond 56 days of continuous administration are not available.

This monograph reviews the chemistry, synthesis, and structural pharmacology of noopept; the multifactorial mechanism of action including AMPA receptor modulation, NMDA receptor effects, neurotrophic factor upregulation, HIF-1 activation, and amyloid-beta neuroprotection; the pharmacokinetic profile with emphasis on the cycloprolylglycine metabolite; the preclinical pharmacology across ischemic, neurodegenerative, and traumatic models; the clinical evidence base; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signal; and a comparative assessment of five nootropic alternatives (piracetam, aniracetam, phenylpiracetam, semax, and cerebrolysin) against noopept on five competency standards.