Azetirelin
A longer-acting, far more potent copy of the brain tripeptide TRH, developed for head and spinal-cord injury and for memory, that did not reach approval
Thyrotropin-releasing hormone (TRH) is a tiny three-amino-acid brain peptide. Beyond its hormone job of telling the pituitary to release thyroid-stimulating hormone, it has a second life as a general central stimulant and nerve protector, which made it and its chemical relatives candidates for brain injury, spinal injury and dementia. Natural TRH is gone in minutes. Yamanouchi built azetirelin (YM-14673) by swapping TRH's front end for a small ring, which made it last longer and act 10 to 40 times more strongly in the brain. In animals it improved recovery after head and spinal-cord trauma and strengthened the brain signalling tied to memory. It reached early clinical testing but was not developed to approval, and it is not a marketed medicine.
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What is it?
TRH is three amino acids long, and for its size it does a surprising amount. Its classic job is to sit at the top of the thyroid axis, telling the pituitary to release thyroid-stimulating hormone. But injected into the brain it also acts as an arousal and protective signal: it counters sedation, raises alertness, and limits some of the damage that follows a blow to the brain or spinal cord. Those actions, not the thyroid one, are what drew drug developers to TRH and its analogues.
The problem with TRH itself is that it is destroyed within minutes and its thyroid effect gets in the way. The analogues were designed to last longer and to separate the brain actions from the hormone action. Azetirelin, coded YM-14673 by Yamanouchi, does this by replacing TRH's front residue (the pyroglutamyl group) with a small four-membered ring. In animal tests it was 10 to 40 times more potent than TRH at reversing the sleep and low body temperature caused by sedatives and alcohol, and it sped recovery of consciousness after experimental head trauma.
Its most developed story was injury. In rats with standardised brain or spinal-cord trauma, azetirelin improved the outcome in a dose-dependent way, part of a body of work on TRH analogues as acute neuroprotectants. A separate line looked at memory: in slices of guinea-pig hippocampus the drug strengthened long-term potentiation, the lasting boost in nerve-cell signalling that underlies learning, which fit its ability to improve experimentally induced memory problems.
Like TRH, it also touched the brain's dopamine system, raising spontaneous movement and exploratory behaviour in rodents, though without the stereotyped licking and biting that stronger dopamine drugs cause. Because it is a peptide and poorly absorbed, much of the later work was pharmaceutical: how to get it into the body, including nasal formulations with absorption enhancers and attempts at an oral form.
Azetirelin reached early clinical testing but was not taken to approval, and its development did not continue. No study of azetirelin in people is published in PubMed, so its whole published record is the preclinical work above. Of the TRH analogues, taltirelin reached approval in Japan for spinocerebellar degeneration, while most others, azetirelin among them, did not. It is of research interest only, is not a medicine, and nothing here is a dose to use.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Mechanism of Action
Azetirelin is a sturdier, stronger copy of TRH aimed at TRH's effects in the brain rather than its thyroid effect. Exactly which receptors carry each action is only partly worked out.
TRH's central actions
TRH has arousal, antidepressant-like and neuroprotective actions in the brain separate from its thyroid role. Azetirelin reproduces these more strongly: 10 to 40 times TRH's potency at reversing sedative effects in animals (PMID 3125485).
Synaptic strengthening
It augmented long-term potentiation in hippocampal slices (PMID 1403605) and raised dopamine-linked activity in rodents (PMID 1973117), actions consistent with its reported improvement of experimental memory problems and its testing in brain injury.
Published Research
These are studies of azetirelin read from their PubMed abstracts on November 5, 2026. The published record is preclinical: brain and spinal-cord injury models, central-nervous-system and dopamine effects compared with TRH, memory-related signalling in brain slices, and the pharmaceutical work on getting a peptide absorbed. No human study of azetirelin is indexed in PubMed, though the molecule reached phase 2.
Brain and spinal-cord injury in rats
In rats given standardised fluid-percussion brain trauma or impact spinal-cord trauma, azetirelin improved the outcome in a dose-dependent way. The paper notes that the molecule is a TRH analogue with its N-terminal pyroglutamyl modified, which makes it longer-acting and much more potent than TRH at central actions. Part of the wider work on TRH analogues as acute treatments for central nervous system injury.
Central-nervous-system effects versus TRH
Compared directly with TRH in mice, azetirelin was 10 to 40 times more potent at reversing the sleep and low body temperature caused by pentobarbital, and the low body temperature caused by alcohol. It sped recovery of consciousness after concussive head trauma and normalised behaviour and brain electrical activity disturbed by a brain lesion, establishing its profile as a potent, long-acting central TRH analogue.
Long-term potentiation in hippocampal slices
In slices of guinea-pig hippocampus, azetirelin (at 0.1 and 1 micromolar) strengthened long-term potentiation in the mossy-fibre pathway in a concentration-dependent way, an effect comparable to a reference agent. Long-term potentiation is the lasting increase in nerve-cell signalling thought to underlie learning, so the result fit the drug's ability to improve experimentally induced memory problems.
Effects on the dopamine system
In rodents, azetirelin at 1 milligram per kilogram raised spontaneous motor activity in rats and induced sniffing and climbing in mice, behaviours linked to the brain's dopamine system, but did not cause the stereotyped licking and biting seen with strong dopamine stimulants even at much higher doses. Its profile resembled TRH's rather than a direct dopamine drug's.
Getting a peptide absorbed through the nose
A pharmaceutical study of a nasal formulation of azetirelin in rats. Because the peptide is poorly absorbed and unstable, the work measured its nasal absorption and showed that adding acylcarnitines to the formulation enhanced it, and estimated the formulation's shelf life from accelerated storage data. Representative of the later effort to find a usable way to deliver the drug.
Side Effects & Contraindications
Reported Side Effects
From preclinical studies only; there is no human safety record for azetirelin in PubMed.
Contraindications & Cautions
Azetirelin has no label and no approved use. These points come from its class and the preclinical work.
Legal Status
Azetirelin is an investigational compound that was never approved in any country and is not marketed.
Frequently Asked Questions
?What is azetirelin?
An experimental drug, coded YM-14673, that is a longer-acting, more potent copy of the brain tripeptide TRH (thyrotropin-releasing hormone). It was studied mainly for brain and spinal-cord injury and for memory.
?Was it ever approved?
No. Azetirelin reached early clinical testing (ChEMBL records phase 2) but was not developed further and was never approved or marketed anywhere.
?Is there human evidence?
Not in the published literature indexed by PubMed, which is all animal and laboratory work. The ChEMBL record shows it reached phase 2, but no human study of azetirelin is indexed, so this page describes the preclinical evidence only.
?How is it related to TRH and taltirelin?
All are TRH-based. TRH is the natural three-amino-acid hormone; azetirelin and taltirelin are analogues built to last longer and act on the brain. Taltirelin reached approval in Japan for spinocerebellar degeneration; azetirelin did not.
?Is it available to buy?
No. Azetirelin is not a medicine and is not sold as one. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [animal] Faden AI. "TRH analog YM-14673 improves outcome following traumatic brain and spinal cord injury in rats: dose-response studies." Brain Res, 1989;486(2):228-35. PMID: 2499400.
- [animal] Yamamoto M, et al. "Effects of a new TRH analogue, YM-14673 on the central nervous system." Naunyn Schmiedebergs Arch Pharmacol, 1987;336(5):561-5. PMID: 3125485.
- [animal] Ishihara K, et al. "YM-14673, a new thyrotropin-releasing hormone analog, augments long-term potentiation in the mossy fiber-CA3 system of guinea pig hippocampal slices." J Pharmacobiodyn, 1992;15(2):75-8. PMID: 1403605.
- [animal] Yamamoto M, et al. "Central dopaminergic actions of YM-14673, a new TRH analogue, in rodents." Eur J Pharmacol, 1990;180(2-3):319-24. PMID: 1973117.
- [animal] Kagatani S, et al. "Nasal absorption kinetic behavior of azetirelin and its enhancement by acylcarnitines in rats." Pharm Res, 1998;15(1):77-81. PMID: 9487550.
- [other] FDA Global Substance Registration System, Azetirelin, UNII 70J5AWG54Q (INN 6363, CAS 95729-65-0, PubChem 65841, NCI Thesaurus C76367; code YM-14673), read November 5, 2026: a thyrotropin-releasing hormone analogue, N-alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate. https://gsrs.ncats.nih.gov/ginas/app/beta/substances/70J5AWG54Q
- [other] ChEMBL molecule CHEMBL2104559 (AZETIRELIN), read November 5, 2026: synonyms Azetirelin, Azetirelina, YM-14673; highest clinical phase recorded 2, no first approval. https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2104559/
- [other] US FDA, Drugs@FDA and the drug label endpoint (openFDA), searched November 5, 2026: no application and no label record for azetirelin. It has an FDA substance record (UNII 70J5AWG54Q) and an INN.
- [registry] ClinicalTrials.gov API v2, searched November 5, 2026: 0 records for azetirelin or YM-14673. The registry began in 2000, after the drug's 1980s-90s development, so the absence is expected. https://clinicaltrials.gov/search?term=azetirelin
Sources & Citations
The five preclinical studies carded above and the References-only drug-profile note were read from their PubMed records on November 5, 2026. Structure, codes and identifiers come from the FDA Global Substance Registration System (UNII 70J5AWG54Q) and ChEMBL (CHEMBL2104559); the absence of approval from Drugs@FDA and openFDA, and of registered trials from ClinicalTrials.gov, all checked the same day. 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. Consult a licensed healthcare provider before making health decisions.