Noogutyl (Nooglutyl)

Chemical identity, and a spelling that returns nothing

The spelling has to be settled before anything else. A PubMed search on the string Noogutyl returns no records, and the query translator reports the phrase as not found; Europe PMC returns zero for the same string. The indexed literature sits under Nooglutil, with Nooglutyl as a variant transliteration and ONK-10 as the original laboratory code, and all three resolve to one deposited structure. PubChem CID 147523 carries CAS 112193-35-8, molecular formula C11H12N2O6, molecular weight 268.22, InChIKey XFZGYOJFPGPYCS-QMMMGPOBSA-N and the IUPAC name (2S)-2-[(5-hydroxypyridine-3-carbonyl)amino]pentanedioic acid. The FDA Global Substance Registration System holds the same molecule under UNII 09UM5JOS3W with the matching CAS. The registry sources queried agree on formula, mass, CAS and InChIKey once the spelling is corrected.

The molecule is 5-hydroxynicotinic acid joined through an amide bond to the alpha-amino group of L-glutamic acid. That construction is the one used in picamilon, which is nicotinic acid amide-linked to GABA (PubChem CID 60608, C10H12N2O3, 208.21). The resemblance is architectural rather than pharmacological, since the amino acid differs and so does the pyridine substitution, and no study located this session compared the two head to head. ChEMBL returned no molecule record for either name, so no curated bioactivity table exists there to consult.

A second registry entry matters more than it first appears. GSRS also holds NOOGLUTYL CALCIUM under UNII AHS2YHS2MG, CAS 2365144-97-2, PubChem CID 86634601, formula C11H10N2O6.Ca at 306.29 g/mol, which is the monocalcium salt of the same acid. That salt is the active substance in a registered Russian intravenous medicine, and it is the form on which every published human trial and most of the work published since 2018 was run. The two are indexed separately, and a commercial drug-intelligence aggregator consulted this session still lists the free acid at preclinical stage with no active indication, which is accurate for the free acid and misleading about the series.

What the original characterisation measured

Voronina and colleagues introduced the compound in Farmakologiia i Toksikologiia in 1990 under the code ONK-10. Working in mice and rats, they reported pronounced antiamnestic and antihypoxic effects, no disturbance of conditioned reflex activity or orientation behaviour, no anxiolytic or anticonvulsant activity, no disorder of movement coordination, and low toxicity. The comparison drawn was that ONK-10 exceeded piracetam, meclofenoxate and demanol aceglumate on the antiamnestic and antihypoxic measures and was not inferior to aniracetam. The retrieved abstract carries no numbers, no group sizes and no LD50, so the characterisation is directional rather than quantitative.

A Soviet-Bulgarian collaboration published the following year in Acta Physiologica et Pharmacologica Bulgarica gives the first dose figures in English. ONK at 50 mg/kg intraperitoneally, given once daily for five days before training, was reported to antagonise scopolamine-provoked amnesia completely in step-through-trained mice, and to abolish the memory-impairing effect of clonidine in shuttle-box rats and of methergoline in step-down rats. The comparators were piracetam at 600 to 800 mg/kg and meclofenoxate at 100 mg/kg, both oral. Sample sizes are absent from the retrieved report, and the authors attributed the effect to cholinergic, noradrenergic and serotonergic transmission without measuring any of the three.

Three developmental models followed from the same institution, the Institute of Pharmacology in Moscow, which a 2003 review by Voronina names as the origin of this compound alongside mexidol and noopept (PMID 12962041). Trofimov and colleagues gave ethanol at 5 g/kg per day by mouth to pregnant rats and reported that 25 mg/kg per day of the compound, administered to the offspring from day 8 to day 20 of life, prevented the delayed impairments in open-field habituation, shuttle-box acquisition and retention, EEG slow-wave power and cortical serotonergic function. The same group used a prenatal hypoxia model, two hours of hypobaric exposure at a vacuum equivalent to 8500 metres on day 15 of intrauterine life, and reported that 25 mg/kg per day given intracutaneously from day 8 to day 20 of life prevented open-field hyperactivity and deficits in training, alternation, passive and active avoidance, and normalised first-month growth (PMID 8704601). Kovalev and colleagues perfused isolated striata from 20-day-old rats and reported that basal and potassium-evoked dopamine efflux, depressed by prenatal ethanol, was normalised by the compound at 25 mg/kg subcutaneously, while the effect in unexposed offspring ran in the opposite direction.

Not every behavioural readout was positive. Inozemtsev and colleagues compared the compound with piracetam across three operant paradigms in rats and reported that neither drug affected the avoidance response in a shuttle box or a T-maze reflex rewarded with water. What separated them was narrow: the compound enhanced escape and avoidance responses in the Skinner box while piracetam improved only the escape response. Reading that paper alongside the amnesia-reversal work gives the shape of the whole rodent record, which is stronger where a deficit has been induced than where behaviour is intact.

The receptor claim, and what the assay measured

Firstova and colleagues ran the only direct receptor experiment located. Using radioligand binding on rat brain membranes in vitro, they reported that the compound competed with the selective AMPA agonist [G-3H]Ro 48-8587 with an IC50 of 6.4 plus or minus 0.2 micromolar, and that noopept competed for the same sites an order of magnitude more weakly at 80 plus or minus 5.6 micromolar. Semax was moderately competitive at metabotropic glutamate sites at 33 plus or minus 2.4 micromolar and dimebon at the NMDA channel site at 59 plus or minus 3.6 micromolar, while piracetam, phenotropil, meclofenoxate and pantogam did not affect binding across a concentration range from 10 to the minus four down to 10 to the minus ten molar. That assay measured competition with an agonist radioligand, which locates binding at or near the agonist site; no modulator-site, desensitisation or deactivation-kinetics protocol was run in it, and a PubMed search pairing the compound name with the word allosteric returns zero records.

Electrophysiology in the series disagrees with itself. Motin and colleagues, in rat hippocampal slices in 2000, reported that high concentrations of the free acid and of mexidol suppressed both orthodromic and antidromic population responses in CA1 evoked by paired stimulation, with orthodromic responses the more sensitive, and that AP7, an NMDA antagonist, blocked both effects. The same first author in 2018, working with the calcium salt in Wistar rat slices, reported the opposite direction: concentrations of 500 micromolar and 1, 2 and 10 millimolar facilitated transmission from Schaffer collaterals to CA1 pyramidal neurons, maximally at 2 millimolar, and 10 millimolar provoked epileptiform activity that MK-801 prevented. Preparation, salt form and concentration range all differ, and no paper located reconciles the two.

A 2026 Russian-language review by Kiselev and colleagues describes the facilitation result as having been obtained in vivo. The study it summarises used surviving hippocampal slices. Elsewhere in the same abstract the review states that radioligand analysis confirmed binding to AMPA receptors, which the 2011 experiment supports, and calls the compound a positive allosteric modulator, which the 2011 experiment does not establish. One older paper is adjacent: Abramets and colleagues in 1995 reported that N-5-oxynicotinoyl glutamate, along with piracetam, ethymisole and a beta-carboline, enhanced NMDA-induced short-term potentiation of population EPSP amplitude in CA1, an effect diminished by protein kinase inhibitors. Short-term potentiation is the measured quantity there, and long-term potentiation is not.

Three further studies bear on mechanism from different angles. Iasnetsov and Krylova tested nine nootropic substances across amnesia induced by microwave irradiation, acute hypoxia and motion sickness, and concluded that the antiamnestic effect of this compound and of the 3-hydroxypyridine derivative SK-170 was caused to a significant degree by activation of non-NMDA receptors, chiefly AMPA, while mexidol's effect ran through GABA-A (PMID 24555225). Voronina and colleagues reported that 70 mg/kg intraperitoneally reduced anxiety in the Vogel conflict test in rats after 24-hour withdrawal from 45 days of diazepam at 4 mg/kg, that concentrations from 5 nanomolar to 750 micromolar did not affect 3H-spiperone binding in vitro, and that 50 mg/kg in vivo raised both the dissociation constant and the density of striatal D2 receptors while 100 mg/kg abolished that change. Firstova and colleagues reported a null result in 2009: after subchronic dosing, hippocampal and cortical BDNF was unchanged in mice of both high and low exploratory efficacy, while piracetam, phenotropil, semax and meclofenoxate each raised hippocampal BDNF in the low-efficacy animals from 0.091 to between 0.115 and 0.123 picograms per microgram (PMID 20095391).

Injury, ischaemia and mitochondrial readouts

Povarova and colleagues produced the most quantitative animal result in the series. Seventy-two hours after occlusion of the distal branch of the middle cerebral artery, the ischaemic zone in rat frontoparietal cortex measured 22.51 plus or minus 3.0 per cent of ipsilateral hemisphere volume. The compound at 10 mg/kg, given into the vein at the moment of occlusion and intraperitoneally for two days after, was reported to restrict that zone to 7.6 plus or minus 2.28 per cent; mexidol at 100 mg/kg gave 9.55 plus or minus 1.9 per cent and phenyl-tert-butylnitrone at the same dose 12.8 plus or minus 1.7 per cent. Retrieval of a previously learnt passive avoidance response was reported as improved in the treated animals. Group sizes are not stated in the retrieved report, and no statistical comparison between the three active arms is described.

Garibova and colleagues used a haemorrhagic model in rats, a post-traumatic haematoma produced by destroying cerebral tissue in the internal capsule region. Single intraperitoneal injections of 10 and 20 mg/kg given three to four hours after the operation were reported to reduce neurological deficiency, restore coordination of movement, improve passive avoidance retrieval and prevent loss of animals (PMID 12924225). Numbers per group are again absent from the retrieved abstract, and the survival claim is stated without a count.

Novikov and Kovaleva measured mitochondrial function rather than behaviour, by polarography of brain mitochondria after open craniocerebral trauma. In their 1997 report, 50 mg/kg prevented the inhibition of respiration seen at 24 hours and was described as more effective than picamilon at 500 mg/kg and pyriditol at 100 mg/kg. Their 1998 study followed one-month-old rats at 1, 4 and 7 days and 4 weeks after trauma, using 25 mg/kg alongside six comparators, and reported that this compound exceeded all of them on the efficiency of oxidative phosphorylation in immature animals. Those experiments measured oxidative phosphorylation, which is ATP synthesis coupled to respiration. No antioxidant endpoint was assayed in either report.

The free acid was also tested in an ageing model. Garibova and colleagues reported that 9-month-old SAMP10 senescence-accelerated mice showed reduced locomotor activity, elevated anxiety and disturbed memory retrieval relative to 3-month-old animals of the same strain, and that the free acid at 20 mg/kg produced changes in the open field, elevated plus maze and passive avoidance tests (PMID 18078032). That report is from 2007, eleven years before the slice work on the salt.

Work on the calcium salt begins later. Kiselev and colleagues reported that the salt at 30 mg/kg was active in the mouse forced swim test, while 0.1 mg/kg maximally alleviated MPTP-induced parkinsonian signs in C57Bl/6 mice and haloperidol-induced catalepsy in rats (PMID 31745682). Route and group sizes are not stated in the retrieved abstract, and the abstract reports no explanation for the three-hundred-fold difference between the two effective doses.

Pharmacokinetics: two species, no human measurement

Firsov and colleagues published the only study located that reports clearance, distribution volume and half-life in two species after intravenous dosing. Calcium salt was given as a bolus to rats at 20, 100 and 500 mg/kg and to rabbits at 50 mg/kg, with serum concentrations measured by HPLC with fluorimetric detection down to a lower limit of 100 nanograms per millilitre. Kinetics were linear in rats at 20 to 100 mg/kg and nonlinear at 500 mg/kg. Decay was biphasic in both species and fitted to a two-compartment model. Total clearance was 18 millilitres per minute per kilogram in rats and 15 in rabbits, steady-state distribution volume 330 and 880 millilitres per kilogram, mean residence time 0.3 and 1.0 hours, and half-life 0.73 and 2.3 hours. Applying allometric scaling, the authors predicted a human half-life of four hours. One earlier systemic study exists, Boiko and Zherdev in 1991, described below.

That predicted figure has since become a stated product characteristic. Russian prescribing information for the intravenous medicine carries a human half-life of approximately four hours, the same number the 2010 allometry produced. No human pharmacokinetic study appears anywhere in PubMed: searches pairing the compound and product names with pharmacokinetics, human, healthy or volunteers return the rat and rabbit paper, the 1991 offspring study, a rabbit formulation paper, a reproductive toxicity paper and a review, and nothing measured in a person. The four-hour figure is a prediction from animal data, and no human measurement stands behind it.

Oral data are thinner still and are routinely misread. Chesnokova and colleagues compared two experimental tablet formulations in rabbits by HPLC and reported that the formulation containing tween-80 achieved 104.3 per cent bioavailability relative to the drug substance. The comparator was the unformulated substance given by the same route, not an intravenous dose, so the figure is a relative bioavailability describing formulation performance rather than the fraction of an oral dose reaching the circulation. Boiko and Zherdev studied ONK-10 kinetics in the offspring of alcoholised rats and reported that long-term administration raised plasma levels and lowered clearance and distribution volume in the offspring of intact animals, while in alcohol-exposed offspring plasma levels fell alongside an increased elimination constant, increased biotransformation and the appearance of a main metabolite, which the abstract does not name (PMID 1786827).

Safety pharmacology amounts to one study. Kiselev and colleagues assessed the calcium salt at 6.7 mg/kg, described as ten times the maximum human therapeutic dose, and reported no effect on reproductive function and no embryotoxic or teratogenic effect. The species is rats, stated in the record's title; the abstract body says only experimental animals, and gives no strain, no sex and no group sizes, and reports a single dose level. There is no located repeat-dose toxicology, no carcinogenicity work, no genotoxicity battery and no juvenile toxicity study for either form.

The human trials were run on the calcium salt

Human evidence begins in 2019 and belongs entirely to the intravenous salt. Kiselev and colleagues ran a randomised, double-blind, placebo-controlled study in 80 patients aged 50 to 75 with chronic cerebrovascular accident attributed to arterial hypertension or atherosclerosis of the main arteries of the head, using daily intravenous doses of 5, 10 or 25 milligrams for 15 days against 0.9 per cent sodium chloride (PMID 31156217). The reported conclusion covered depression, sleep quality and cognitive function. Effect sizes, scale names and per-arm allocation are absent from the retrieved abstract, so the study is legible as a design and not as a set of numbers.

Skoromets and colleagues published the confirmatory trial two years later, typed by PubMed as a Phase III randomised controlled multicentre study. One hundred and twenty-four patients aged 50 to 75 with chronic cerebrovascular disorders were allocated 62 to 25 milligrams by slow intravenous bolus for 15 days and 62 to saline placebo. The primary endpoint, a rise of two or more points on the Montreal Cognitive Assessment, was reached by 83.87 per cent of the treated group and 22.58 per cent of controls. Adverse events occurred in 14.52 per cent against 8.06 per cent, a difference the authors reported as not significant at p equals 0.395. The report states that all 124 patients completed every visit with no dropouts.

Everything published since is open-label, uncontrolled, or controlled only against standard care. Kotov and colleagues compared 30 patients given 25 milligrams intravenously fifteen times during post-stroke rehabilitation against 30 who were not, reporting a mean two-point MoCA rise in the treated group and no significant change in the untreated group (PMID 34932282); a later report from the same group covered 140 patients of whom 78 received the drug, with a MoCA rise in 87.2 per cent against 38.7 per cent (PMID 37682099). Zhitkova and colleagues followed 50 patients with mild cognitive impairment in chronic cerebral ischaemia through a single-arm observational course at 25 milligrams daily for 15 days (PMID 37966443). Khokhlov and colleagues randomised 203 post-stroke patients, 102 to drug plus standard therapy and 101 to standard therapy alone; randomisation is reported, but the comparison is open-label with no placebo arm and no blinding described (PMID 41524353). Every one of these was conducted in Russia and published in one journal.

Registry and legal position follow. ClinicalTrials.gov intervention searches on nooglutil, nooglutyl, the trade name and hydroxynicotinoyl return zero studies each, so none of the trials above is registered there. openFDA returns no label and no application for the name, and neither the free acid nor the salt is approved by the FDA or the EMA. The calcium salt does hold a Russian marketing authorisation as a 5 milligram per millilitre intravenous solution for chronic cerebrovascular insufficiency, but the certificate could not be confirmed against the state register itself, which returned a redirect, and one mirror was refused outright. Two mirrors disagree: one gives certificate LP-006394 with a February 2023 approval and a lapsed status, another gives LP-N(002862)-(RG-RU) issued 25 July 2023 and valid to 25 July 2028. The free acid sold as powder is a registered medicine nowhere located.

What is not known

No human exposure to the free acid is recorded anywhere in the literature. Every trial located used the calcium salt intravenously, in Russia, published in one journal, and none is registered on ClinicalTrials.gov, so no protocol, no statistical analysis plan and no independent audit trail is available for any of them. Human pharmacokinetics has never been measured; the four-hour half-life in circulation is an allometric prediction from a rat and rabbit study. Safety characterisation consists of a single reproductive-toxicity report at one dose level in rats, with strain, sex and group sizes unstated, and no repeat-dose, genotoxicity, carcinogenicity or juvenile toxicology located for either form. Brain concentration has never been quantified in any species, so the assumption of central penetration rests on behavioural inference. Sample sizes are absent from the great majority of the rodent reports, which are mostly English abstracts of Russian-language papers whose methods sections were not retrievable this session. The receptor picture is unresolved: one competitive binding assay, two slice studies from the same laboratory reporting opposite directions of effect on different salts, and no allosteric-site experiment, despite the positive-modulator description being asserted as a premise in the primary literature since 2002. Whether the free acid and the calcium salt behave equivalently at the receptor or in the body has not been tested directly.

Questions