Posatirelin
A Hungarian TRH-analogue tripeptide given by daily injection in 1990s trials for Alzheimer's and vascular dementia, then abandoned
Posatirelin, coded RGH-2202, is a three-amino-acid peptide built by Gedeon Richter on the template of thyrotropin-releasing hormone (TRH), changed so that it keeps TRH's stimulating effects on the brain while losing most of its thyroid-hormone action. In Italian multicentre trials in the mid-1990s, three months of daily intramuscular injections improved dementia rating-scale scores in people with Alzheimer's disease and vascular dementia. No trial has been published since 1998 and it was never approved anywhere.
Used in human trials: 10 mg, Once daily, Intramuscular (Study: pharmacokinetics in healthy elderly volunteers) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
Work out syringe units → · New to syringes? · All dosing data ↓
What is it?
Thyrotropin-releasing hormone is a three-residue peptide best known for telling the pituitary to release thyroid-stimulating hormone, but injected into animals it also wakes the brain up: it raises alertness, counters sedatives and stimulates breathing. Those central effects interested drug chemists for decades, and the obstacle was always that TRH also drives the thyroid and is broken down within minutes. In the 1980s chemists at Gedeon Richter in Budapest swapped TRH's first and middle residues and found that replacing pyroglutamic acid with the one-carbon-longer pyro-2-aminoadipic acid, with leucine in the middle, gave the strongest effect on the brain with almost no hormone release. That compound, RGH-2202, became posatirelin.
In rodents it behaved like a stronger, longer-lasting TRH. A 1989 comparison found it two to five times better than TRH at reversing avoidance-learning deficits in mice and about thirty times weaker at releasing thyrotropin. Over the next decade rat studies reported that it shortened recovery from experimental stroke, reversed drug- and age-related memory loss, protected the hippocampus from kainate seizures, raised blood pressure and survival in haemorrhagic shock, and partly restored cholinergic nerve fibres after brain lesions. In nerve-cell cultures it sped up maturation and protected cells against several toxins.
The human work was done mostly in Italy. A 1996 study in healthy elderly volunteers gave 10 mg a day into the muscle for a week, found no accumulation, no clinically relevant change in thyroid hormones and no significant side effects, though thyroid-stimulating hormone drifted down. Three multicentre double-blind trials followed. In late-onset Alzheimer's disease it beat citicoline and an inactive comparator, vitamin C, on several subscales of the Gottfries-Bråne-Steen dementia scale. In vascular dementia it beat placebo on the same scale and on memory tests, and the gap was still there a month after treatment stopped. The largest trial, 360 patients with either type of dementia, again favoured posatirelin over placebo, with adverse events in 7.3% of those treated and no difference in safety measures.
Those results did not lead to a medicine. The abstracts report that differences were statistically significant but do not say how large they were, so a reader cannot judge whether the gains mattered in daily life, and the treatment needed an injection every day for months. A 2004 review of non-cholinergic drugs in vascular dementia placed posatirelin among several that showed some, partly limited, benefit, and blamed many disappointing trials in that field on mixed patient groups, small samples and tests borrowed from Alzheimer's research. Gedeon Richter's own 2002 overview is the last summary from the developer; we found no registered trial and no study in people after 1998.
Before the dementia work, posatirelin was tried for a different purpose. A 1991 Russian report gave it under the name Piladox to 75 patients coming round from general anaesthesia, where an intravenous infusion deepened and quickened breathing without undoing the pain relief of opioids, matching rat studies in which it reversed morphine's suppression of the diaphragm. Two other members of the family have entries here: protirelin, which is TRH itself, and taltirelin, a long-acting analogue that reached the market in Japan.
Mechanism of Action
Posatirelin was designed to keep the brain effects of TRH while shedding its hormone effects. The papers describe actions on several transmitter systems rather than one receptor, and none establishes which of them matters in people.
Arousal and catecholamines
Like TRH, it raised noradrenaline and dopamine turnover in mouse and rat brain and increased wakefulness, but with about a thirtieth of TRH's thyrotropin-releasing activity (1989 study).
Cholinergic neurons
After lesions of the nucleus basalis in rats, eight weeks of treatment preserved more acetylcholine-making neurons and partly restored cholinergic fibres in the frontal cortex (1997 and 1998 studies).
Nerve-cell growth and survival
It sped up the maturation of cultured cerebellar neurons by amplifying NMDA-receptor signalling (1992) and protected cultured human and mouse neurons against toxins (2009 and 2010).
Breathing
It stimulated the diaphragm and reversed morphine-induced breathing depression in rats without blocking pain relief, an effect that NMDA-receptor blockers abolished (1990 and 1991 studies).
Published Research
These are the studies of posatirelin read from their PubMed abstracts on October 29, 2026: five in people, two reviews, thirteen in animals and three in cultured cells. Rat papers often call it RGH-2202 or give its chemical name, L-6-ketopiperidine-2-carbonyl-leucyl-prolinamide, which is the same molecule; several are carded because their abstracts name it as the compound given.
360 patients with Alzheimer's or vascular dementia
After a two-week placebo run-in, patients received posatirelin or placebo by daily intramuscular injection for three months. On both intention-to-treat (357) and per-protocol (260) analyses, posatirelin did better on the Gottfries-Bråne-Steen scale and the Rey memory test, equally in both dementia types. Adverse events occurred in 7.3% of the posatirelin group, with no difference in safety measures between groups.
Vascular dementia against placebo
A multicentre double-blind trial gave daily intramuscular injections for 12 weeks after a placebo run-in. Treated patients improved on intellectual performance, orientation, motivation and memory items of the GBS scale and on the Randt memory test, and the difference persisted one month after stopping. Tolerability was good.
Late-onset Alzheimer's against citicoline
Elderly patients received posatirelin, citicoline (the reference drug) or vitamin C (the inactive comparator) by daily injection for three months, then one month of oral placebo. Posatirelin scored better on GBS subscales covering intellect, emotion, orientation, memory, daily activities and motivation. The authors called for larger trials.
Pharmacokinetics in healthy elderly people
Healthy elderly volunteers received 10 mg a day by intramuscular injection for seven days. Kinetics on day 7 matched day 1, so the drug did not accumulate. Basal and peak TSH fell progressively while free T3 and T4 stayed normal and cortisol and prolactin rhythms were unchanged. No significant adverse effects were seen.
Breathing after general anaesthesia (as Piladox)
In 75 patients waking from anaesthesia, an intravenous infusion of 1 mg/kg increased breathing rate and volume, bringing carbon dioxide back to its starting level, with stable circulation. It did not weaken the pain relief of the opioids used. Animal work in the same report found it a stronger respiratory stimulant than nikethamide.
The developer's overview
Gedeon Richter scientists summarise why RGH-2202 was chosen: stronger alertness effects than TRH in mice, rats and cats, benefit in models of impaired consciousness and memory, nerve-growth effects, and almost no hormonal action. They report improvement in every well-controlled dementia trial.
Non-cholinergic drugs for vascular dementia
A critical review of randomised trials places posatirelin with nicergoline, memantine, propentofylline and pentoxifylline as drugs with some, partly limited, benefit, and blames many negative trials on mixed patient groups, small samples and tests borrowed from Alzheimer's research.
Cholinergic neurons after brain lesions
In rats with lesions of the nucleus basalis, eight weeks of posatirelin left more choline-acetyltransferase-positive neurons, restored cholinergic fibres in the frontal cortex and partly restored acetylcholinesterase staining; sham-operated rats were unaffected.
Nucleus basalis lesions, 10 mg/kg a day
At 10 mg/kg a day for 4 or 8 weeks it did not change neuron or astrocyte counts but increased nerve fibres in the hippocampus and partly restored cholinergic markers in the frontal cortex of lesioned rats, mainly after eight weeks.
Locus coeruleus lesions
After lesions of the noradrenaline-producing locus coeruleus, eight weeks of 10 mg/kg a day increased frontal-cortex neurons and fibres in one-sided lesions but did not restore tyrosine hydroxylase staining.
Learning and movement in old rats
In 24-month-old rats, 5 or 10 mg/kg a day for 20 days improved avoidance learning, exploration and rotarod performance; it reversed scopolamine amnesia in adult rats and reduced deficits in rats damaged before birth.
Recovery after experimental stroke
After middle cerebral artery occlusion, 14 days of 1-10 mg/kg improved neurological and learning deficits over 35 days, about three times as potently as TRH, and the tissue damage was smaller.
Kainate seizures in mice
At 2.5 and 5 mg/kg it raised the kainate dose needed to cause seizures, and at 2.5-10 mg/kg it reduced hippocampal neuron loss; in rat cortical cultures it also limited kainate toxicity.
Memory and behaviour in rats
Single injections of 5 or 10 mg/kg reduced radial-maze errors and reversed hypoxia-induced amnesia and age-related learning loss; at the same doses TRH was less effective.
Haemorrhagic shock in rats
After half the blood volume was removed, an intravenous dose within five minutes raised blood pressure and survival in a dose-dependent way, more than TRH did.
Memory after internal capsule lesions
Rats with internal capsule lesions lost avoidance learning along with brain dopamine and serotonin; RGH-2202 at 10 mg/kg intraperitoneally or 0.2-1 mg/kg intravenously improved learning, while physostigmine did not.
Diaphragm activity and morphine
Given intravenously or onto the brainstem of anaesthetised rats it stimulated the diaphragm and reversed morphine's depression of it, with timing close to TRH's; NMDA-receptor blockers prevented both effects.
Opioid breathing depression
At 1-5 mg/kg intravenously it abolished fentanyl- and morphine-induced breathing depression in rabbits and rats without reducing morphine's pain relief; 10-40 mg/kg did not change blood pressure or heart rate.
Pharmacological profile against TRH
In mice and rats it reproduced TRH's stimulant effects, enhanced noradrenaline and dopamine turnover and was two to five times stronger against avoidance deficits, while its thyrotropin-releasing activity was about thirty times weaker.
Synthesis of the series
Of 17 TRH analogues made by changing both ends of the molecule, the strongest central anticataleptic effect with negligible hormone release came from pAad-Leu-Pro-NH2, RGH 2202.
Maturation of cultured neurons
Daily RGH-2202 sped up the maturation of cultured rat cerebellar granule cells more than TRH and amplified NMDA-receptor-driven signalling, without acting on glutamate uptake directly.
Human neuroblastoma cells
In differentiated human SH-SY5Y cells, RGH-2202 at micromolar concentrations reduced damage from several toxins, including beta-amyloid, and its protection against staurosporine depended on the PI3-kinase pathway and raised Bcl-2.
Mouse cortical neurons
Pre-treatment protected cortical neurons from excitatory amino acids, hydrogen peroxide and staurosporine, but RGH-2202 was the weakest of the four TRH-type peptides tested.
Dosing Data
Posatirelin was never approved, so there is no label. The rows below are amounts stated in the abstracts of published human studies. The dementia trial abstracts give the schedule, once-daily intramuscular injection for three months, but not the amount, so no row is written for them.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Posatirelin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
An arithmetic example, not a recommendation: a 10 mg vial mixed with 3 mL of bacteriostatic water holds 3,333.3 mcg per mL, so 10 mg, the “Study: pharmacokinetics in healthy elderly volunteers” row would be 300.0 units, more than a 1 mL U-100 syringe holds. Put your own vial's numbers into the reconstitution calculator.
Source: dose: Used in human trials, PMID 8889903 (Dosing Data below); vial and water: the calculator's default example, not a vial size we have a source for.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Posatirelin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Posatirelin stays intact once mixed.
How it is taken
As it was given in human studies: Intramuscular (Once daily; Study: pharmacokinetics in healthy elderly volunteers); Intravenous (Single infusion; Study: breathing after general anaesthesia (as Piladox), 75 patients).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Study: pharmacokinetics in healthy elderly volunteers: 7 days; Study: breathing after general anaesthesia (as Piladox), 75 patients: Once, on waking.
When effects appear: unknown; no source on this page gives a time to effect for Posatirelin. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: Adverse events in 7.3% of patients on posatirelin in the 360-patient trial, with no difference in safety measures from placebo (PMID 18653124); A progressive fall in thyroid-stimulating hormone over a week of 10 mg a day, with free T3 and T4 staying normal (PMID 8889903); Tolerability described as good in both earlier dementia trials, without figures (PMIDs 7484061, 8836309). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Posatirelin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the trial abstracts read, which give few safety details”).
Interactions
Unknown: a PubMed search for human interaction studies of Posatirelin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Posatirelin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Posatirelin's expected mass, 352.4 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Discontinued (Never approved: Drugs@FDA and the EMA medicines list hold no record (searched October 28, 2026), and ClinicalTrials.gov lists no trial). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the trial abstracts read, which give few safety details.
Contraindications & Cautions
No product label exists. These cautions follow from the evidence.
Legal Status
Posatirelin reached multicentre trials in Italy in the 1990s and was never approved.
Frequently Asked Questions
?What is posatirelin?
A synthetic three-amino-acid analogue of thyrotropin-releasing hormone, coded RGH-2202, designed to keep TRH's stimulating effects on the brain while losing most of its thyroid-hormone action.
?Did it work for dementia?
Three Italian double-blind trials in the 1990s, the largest with 360 patients, reported better scores on a dementia rating scale and memory tests than placebo or comparators. The abstracts give significance, not effect sizes, and no trial was run after 1998.
?How was it given?
By intramuscular injection once a day, for three months in the dementia trials. A safety study in healthy elderly volunteers used 10 mg a day for a week.
?Is posatirelin approved anywhere?
No. We found no approval in the US, the EU or elsewhere, and no trial registration.
?How does it differ from taltirelin and protirelin?
Protirelin is TRH itself. Taltirelin is another long-acting TRH analogue, approved in Japan. Posatirelin is a third analogue from Hungary that stopped at the trial stage. Each has its own entry.
References
- [other] PubChem CID 71230, Posatirelin: formula C17H28N4O4, molecular weight 352.4. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/71230
- [other] ChEMBL CHEMBL2105243, posatirelin: maximum clinical phase 2 in the ChEMBL molecule record, read October 2, 2026 (the Registry's ChEMBL harvest). https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2105243/
- [clinical-trial] Parnetti L, et al. "Posatirelin for the treatment of late-onset Alzheimer's disease: a double-blind multicentre study vs citicoline and ascorbic acid." Acta Neurol Scand, 1995;92(2):135-40. PMID: 7484061.
- [clinical-trial] Parnetti L, et al. "Posatirelin in the treatment of vascular dementia: a double-blind multicentre study vs placebo." Acta Neurol Scand, 1996;93(6):456-63. PMID: 8836309.
- [clinical-trial] Gasbarrini G, et al. "Posatirelin for the treatment of degenerative and vascular dementia: results of explanatory and pragmatic efficacy analyses." Arch Gerontol Geriatr, 1998;26(1):33-47. PMID: 18653124.
- [clinical-trial] Reboldi G, et al. "Pharmacokinetic profile and endocrine effects of posatirelin treatment in healthy elderly subjects." J Clin Pharmacol, 1996;36(9):823-31. PMID: 8889903.
- [clinical-trial] Sachkov VI, et al. "[Stimulation of respiration with Piladox in experimental and clinical conditions during administration of drugs for general anesthesia]." Khirurgiia (Mosk), 1991:90-6. PMID: 1687072.
- [review] Sarkadi A, et al. "[TRH analogs at Gedeon Richter Ltd.: highlights of experimental and clinical efficacy of posatirelin]." Acta Pharm Hung, 2002;72(1):62-8. PMID: 12426788.
- [review] Pantoni L. "Treatment of vascular dementia: evidence from trials with non-cholinergic drugs." J Neurol Sci, 2004;226(1-2):67-70. PMID: 15537523.
- [pubmed] Sabbatini M, et al. "Effect of lesions of the nucleus basalis magnocellularis and of treatment with posatirelin on cholinergic neurotransmission enzymes in the rat cerebral cortex." Mech Ageing Dev, 1998;104(2):183-94. PMID: 9792196.
- [pubmed] Amenta F, et al. "Effect of treatment with the neuroactive peptide posatirelin on microanatomical changes of frontal cortex and hippocampus caused by lesions of the locus coeruleus." Drugs Exp Clin Res, 1997;23(2):77-88. PMID: 9309383.
- [pubmed] Panocka I, et al. "Effect of the thyrotropin releasing hormone analogue posatirelin (RGH 2202) on microanatomical changes induced by lesions of the nucleus basalis magnocellularis in the rat." Drugs Exp Clin Res, 1997;23(1):13-23. PMID: 9093818.
- [pubmed] Drago F, et al. "Effects of RGH 2202 on cognitive and motor behavior of the rat." Neurobiol Aging, 1996;17(1):67-71. PMID: 8786805.
- [pubmed] Noda Y, et al. "Effects of RGH-2202 on behavioral deficits after focal cerebral ischemia in rats." Pharmacol Biochem Behav, 1995;52(4):695-9. PMID: 8587907.
- [pubmed] Jaworska-Feil L, et al. "Protective effects of TRH and its stable analogue, RGH-2202, on kainate-induced seizures and neurotoxicity in rodents." Epilepsy Res, 2001;43(1):67-73. PMID: 11137388.
- [pubmed] Drago F, et al. "Behavioral changes induced by the thyrotropin-releasing hormone analogue, RGH 2202." Peptides, 1991;12(6):1309-13. PMID: 1815218.
- [pubmed] Coppi G, et al. "The thyrotropin releasing hormone analogue, RGH 2202, reverses experimental haemorrhagic shock in rats." Eur J Pharmacol, 1990;182(1):185-8. PMID: 2119310.
- [pubmed] Oka M, et al. "Memory deficits following internal capsule lesions in rats and their improvement by L-6-ketopiperidine-2-carbonyl-L-leucyl-L-proline amide (RGH-2202), a thyrotropin-releasing hormone analogue." Arch Int Pharmacodyn Ther, 1990;306:18-33. PMID: 1981666.
- [pubmed] Kharkevich DA, et al. "Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors." Brain Res, 1991;551(1-2):110-5. PMID: 1833029.
- [pubmed] Chichenkov ON, et al. "[The characteristics of the interaction of the thyroliberin analog RGH 2202 and narcotic analgesics]." Farmakol Toksikol, 1990;53(1):25-7. PMID: 1970308.
- [pubmed] Oka M, et al. "L-6-ketopiperidine-2-carbonyl-L-leucyl-L-proline amide as a novel thyrotropin releasing hormone analogue with improving effects on impaired central nervous systems functions." Arzneimittelforschung, 1989;39(3):297-303. PMID: 2547386.
- [pubmed] Szirtes T, et al. "Synthesis of thyrotropin-releasing hormone analogues. 2. Tripeptides structurally greatly differing from TRH with high central nervous system activity." J Med Chem, 1986;29(9):1654-8. PMID: 3091831.
- [pubmed] Casabona G, et al. "Thyrotropin releasing hormone (TRH) and its analog, RGH-2202, accelerate maturation of cerebellar neurons in vitro." Brain Res Dev Brain Res, 1992;69(2):179-83. PMID: 1424094.
- [pubmed] Jaworska-Feil L, et al. "Protective effects of TRH and its analogues against various cytotoxic agents in retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells." Neuropeptides, 2010;44(6):495-508. PMID: 20869113.
- [pubmed] Jantas D, et al. "Effects of TRH and its analogues on primary cortical neuronal cell damage induced by various excitotoxic, necrotic and apoptotic agents." Neuropeptides, 2009;43(5):371-85. PMID: 19666192.
Sources & Citations
Every study on this page was read from its PubMed record on October 29, 2026. The formula and weight are PubChem's. Regulatory status comes from Drugs@FDA, the EMA medicines list and ClinicalTrials.gov, searched October 28, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.