24305-27-9

Basic information

• Product Name: TRH
• Synonyms: THR 1-2;THR 2-3;PROTIRELIN;PYROGLU-HIS-PRO AMIDE;PYROGLU-HIS-PRO NH2;PYR-HIS-PRO-NH2(TRH);PYR-HIS-PRO-NH2;PGLU-HIS-PRO-NH2
• CAS NO: 24305-27-9
• Molecular Formula: C₁₆H₂₂N₆O₄
• Molecular Weight: 362.38
• EINECS: 246-143-4
• Product Categories: Peptide;THYPINONE
• Mol File: 24305-27-9.mol

Chemical Properties

• Boiling Point: 494°C (rough estimate)
• Flash Point: 545.5 °C
• Appearance: /powder
• Density: 1.1675 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.6000 (estimate)
• Storage Temp.: −20°C
• Solubility: H2O: 10 mg/mL, clear, colorless
• PKA: 13.05±0.20(Predicted)
• Stability: Hygroscopic
• Merck: 13,9663
• BRN: 770238
• CAS DataBase Reference: TRH(CAS DataBase Reference)
• NIST Chemistry Reference: TRH(24305-27-9)
• EPA Substance Registry System: TRH(24305-27-9)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 2
• RTECS: TW3580000
• F: 10-21
• Hazardous Substances Data: 24305-27-9(Hazardous Substances Data)

Usage

Uses

Used in Endocrinology:
Protirelin is used as a diagnostic agent for the assessment of thyroid function. It helps in the evaluation of patients with suspected hypothalamic or pituitary dysfunction by stimulating the release of TSH, PRL, and GH.
Used in Neurology:
As a neurotransmitter and neuromodulator, Protirelin is used in the study and treatment of various neurological disorders. It has been found to have potential therapeutic applications in conditions such as depression, Alzheimer's disease, and spinal cord injuries.
Used in Wound Healing:
Protirelin is used as a therapeutic agent to accelerate wound healing. Its ability to stimulate the release of growth hormone and other factors contributes to the promotion of tissue repair and regeneration.
Used in Anticancer Applications:
Although not explicitly mentioned in the provided materials, Protirelin has been studied for its potential role in cancer treatment. It has been shown to modulate several oncological signaling pathways, which could potentially be harnessed for therapeutic purposes in cancer patients.
Used in Drug Delivery Systems:
Similar to Gallotannin, Protirelin could potentially be incorporated into novel drug delivery systems to enhance its applications and efficacy. These systems could improve the delivery, bioavailability, and therapeutic outcomes of Protirelin in various medical applications.

Discovery

TRH was first isolated and characterized in 1969 by Roger Guillemin and Andrew Schally, who shared the Nobel Prize in Physiology or Medicine in 1977 “for their discoveries concerning the peptide hormone production of the brain.”The biosynthesis of TRH from a precursor molecule was first clarified in 1984 by isolation of a preproTRH cDNA from the skin of Xenopus laevis.? The structure of the TRH receptor (TRH-R) was first deduced from a cDNA isolated from the mouse pituitary in 1990.

Properties

Mr 362. Soluble in water, methanol, and ethanol; partially insoluble in chloroform; completely insoluble in ether and pyridine. Stable in solution at <15°C for more than a year; partially (1%) degraded at 40°C for 6 months. Resistant to proteolytic enzymes. Inactivated by diazotized sulfanilic acid (Pauly reagent). Plasma half-life is 2–6min.

Synthesis and release

TRH secretion is regulated by norepinephrine, histamine, dopamine, and serotonin. Cold-induced secretion of TSH from the rat anterior pituitary involves α-adrenergic regulation of TRH secretion. TRH neurons in the PVN are negatively regulated by thyroid hormones through a feedback mechanism. Locally produced T3 is taken by these neurons to regulate transcription, posttranslational modification, and degradation of TRH.

Gene, mRNA, and precursor

TRH is synthesized from a precursor that contains multiple copies of the TRH progenitor sequence GlnHis-Pro-Gly, which is flanked by dibasic cleavage sites at its N- and C-termini. The number of progenitor sequences in a precursor is diversified: six in humans, five in rats, four in chicken, seven in frogs, and six to eight in fish. Human preproTRH gene, TRH, location 3q13.3–q21, consists of three exons.

Clinical implications

The majority of thyroid disfunction is due to primary thyroid disease. On the other hand, central thyroid disfunction is related to a disorder of the pituitary (TSH), hypothalamus (TRH), or hypothalamic-pituitary portal circulation. Isolated central hypothyroidism was reported in a patient with inactivating mutations in the TRH-R gene.

Receptors

TRH-R is a seven-transmembrane-domain GPCR. Two major types of TRH-Rs (type I receptor including TRH-R1 and TRH-R3, and type II receptor [TRH-R2]), have been identified in vertebrates . Three and four subtypes of TRH-Rs have been identified in Xenopus laevis and teleost species, respectively.?TRH action is mediated via a membrane receptor mainly coupled to Gq/11 protein. TRH induces the mobilization of intracellular Ca2+ and the activation of PKC in target cells.

Biological functions

The Trh knockout mice show normal development, but exhibit tertiary hypothyroidism and hyperglycemia due to diminished insulin secretion. The Trh knockout mice show defects in cerebellar long-term depression and a motor learning deficit.The Trhr1 knockout mice exhibit central hypothyroidism showing a decrease in serum T3, T4, and PRL levels but not in serum TSH?levels. The Trhr1 knockout mice exhibit normal growth and development but displayed increased anxiety and depression levels. The Trhr2 knockout mice are euthyroid with normal serum TSH levels and exhibit normal development and growth. The mutant females exhibited moderately increased depression and reduced anxiety phenotypes.

Indications

Thyrotropin-releasing hormone, or protirelin, consists of three amino acids. TRH (Relefact TRH) is used for tests to distinguish primary from secondary hypothyroidism.

Biochem/physiol Actions

Thyrotropin releasing hormone (TRH) stimulates production and secretion of thyrotropin (TSH) and prolactin from the anterior pituitary. It also plays a vital role as a neurotransmitter and neuromodulator.

Clinical Use

TRH (200–500μg) administered intravenously to normal subjects causes a rise in TSH levels within 15–30min, resulting in an increase in T3 levels within 90–150min. In primary hypothyroidism, TSH hyperresponse to TRH occurs, with a typical elevation in the basal TSH levels. In secondary (pituitary) hypothyroidism, an impaired TSH response to TRH occurs, whereas in tertiary (hypothalamic) hypothyroidism normal or increased TSH response to TRH occurs. Protirelin is used to test the response of the anterior pituitary to TRH in people who may have medical conditions of thyroid function, including hyperthyroidism, Graves’ disease, and hypothyroidism. In addition, TRH has been used to assess the ability of the prolactin secretion in the pituitary.

InChI:InChI=1/C16H22N6O4/c17-14(24)12-2-1-5-22(12)16(26)11(6-9-7-18-8-19-9)21-15(25)10-3-4-13(23)20-10/h7-8,10-12H,1-6H2,(H2,17,24)(H,18,19)(H,20,23)(H,21,25)

Upstream product

• 28613-24-3 Gln-His-Pro-NH₂ 
• 1162640-73-4 Pyroglutamylhistidine 
• 7531-52-4 L-prolinamide 
• 83468-78-4 L-pyroglutamyl-2,5-dibromo-L-histidyl-L-prolineamide 
• 189179-52-0 (S)-2-[(S)-1-[3-(Adamantan-2-yloxymethyl)-3H-imidazol-4-ylmethyl]-2-((S)-2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethylcarbamoyl]-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester 
• 109425-51-6 Fmoc-His(Trt)-OH 
• 98-79-3 L-Pyroglutamic acid 
• 53100-44-0 L-N-t-butoxycarbonylpyroglutamic acid 
• 83480-22-2 N(α)-t-butoxycarbonyl-2,5-dibromo-L-histidyl-L-proline amide 
• 2488-14-4 N-(tert-butoxycarbonyl)-L-histidine methyl ester 
• 71-00-1 L-histidine 
• 17791-52-5 N-(tert-butoxycarbonyl)-L-histidine 
• 15761-39-4 1-(tert-butoxycarbonyl)-L-proline 
• 177609-24-4 (S)-3-[3-(Adamantan-2-yloxymethyl)-3H-imidazol-4-yl]-2-tert-butoxycarbonylamino-propionic acid 

Downstream Products

• 92484-23-6 C₁₇H₂₁F₃N₆O₄ 
• 104987-37-3 C₁₇H₂₁F₃N₆O₄ 

Relevant articles and documents

A novel peptide synthesis using fluorous chemistry.

Three new fluorous supports for peptide synthesis, i.e., the trialkoxybenzhydryl-type (6), the Wang-type (7) and the tert-butyl-type support (8), were prepared. A bioactive peptide TRH was easily synthesized by an Fmoc strategy using the benzhydryl-type fluorous support with fluorous chemistry.

Thyrotropin-releasing hormone loaded and chitosan engineered polymeric nanoparticles: Towards effective delivery of neuropeptides

Thyrotropin-Releasing Hormone (TRH), a tripeptide amide with molecular formula L-pGlu-L-His-L-Pro-NH2, is used in the treatment of brain/spinal injury and certain central nervous system (CNS) disorders, including schizophrenia, Alzheimer's disease, epilepsy, depression, shock and ischemia due to its profound effects on the CNS. However, TRH's therapeutic activity is severely hampered because of instability and hydrophilicity owing to its peptidic nature which results into ineffective penetration into the blood brain barrier. In the present study, we report the synthesis and stability studies of novel chitosan engineered TRH encapsulated poly(lactide-co-glycolide) (PLGA) based nanoformulation. The aim of such an encapsulation is to allow effective delivery of TRH in biological systems as the peptidase degrade naked TRH. The synthesis of TRH was carried out manually in solution phase followed by its encapsulation using PLGA to form polymeric nanoparticles (NPs) via nanoprecipitation technique. Different parameters such as type of organic phase, concentration of stabilizer, ratio of organic phase and aqueous phase, rate of addition of organic phase were optimized, tested and evaluated for particle size, encapsulation efficiency, and stability of NPs. The TRH-PLGA NPs were then surface modified with chitosan to achieve positive surface charge rendering them potential membrane penetrating agents. PLGA, PLGA-TRH, Chitosan-PLGA and Chitosan-PLGA-TRH NPs were characterized and analyzed using Dynamic Light Scattering (DLS), Transmissiom Electron Microscopy (TEM) and Infra-red spectroscopic techniques.

Pressure/Temperature Combined Treatments of Precursors Yield Hormone-like Peptides with Pyroglutamate at the N Terminus

Peptides containing the cyclic product of glutamine at the N terminus are usually biologically active. If the cyclization of glutamine was associated with a volume reduction, pressure should displace the equilibrium in the direction of the lower volume. Here, results in model solutions and in whey are discussed, showing that the theorized cyclization of glutamine in Gln-His-ProNH2 or Gln-Leu-ProNH2 is significantly accelerated during the application of heat and even more strongly when elevated temperature and pressure combinations are used. The reaction rate depended on the intensity of the pressure treatment, the pH, and the nature of the amino acids adjacent to glutamine. The products of the reaction were identified as thyrotropin-releasing hormone (TRH) and [Leu(2)]TRH. The reported reactions could affect the naturally balanced concentration of short-chain peptides in foods and therefore induce unpredictable biological effects.

Amino acids and peptides. L. Development of a novel N(π)-protecting group for histidine, N(π)-2-adamantyloxymethylhistidine, and its application to peptide synthesis

N(α)-tert-Butyloxycarbonyl-N(π)-2-adamantyloxymethylhistidine, Boc- His(N(π)-2-Adom)-OH, was prepared by the reaction of Boc-His (N(τ)-Boc)- OMe with 2-adamantyloxymethyl chloride (2-Adom-Cl), followed by saponification. The 2-Adom group was stable to trifluoroacetic acid (TFA), 1 N NaOH and 20% piperidine/DMF and easily removed by 1M trifluoromethanesulfonic acid-thioanisole/TFA and HF. This new protecting group suppressed racemization during peptide synthesis and exhibited high solubility in organic solvents. It was applied to the synthesis of thyrotropin-releasing hormone (TRH) using both solution and solid-phase methods. The N(π)-2-Adom group can be used for peptide synthesis in combination with the tert-butyloxycarbonyl group as the N(α)-protecting group in both solution and solid-phase methods.

Synthesis of Nπ-2-adamantyloxymethylhistidine, His(Nπ-2-Adom), and its evaluation for peptide synthesis

Nπ-2-Adamantyloxymethylhistidine, His(Nπ-2-Adom), is prepared and successfully applied to the synthesis of thyrotropin-releasing hormone (TRH) in combination with tert-butyloxycarbonyl (Boc) as the Nα-protecting group. This new protecting group suppressed racemization during peptide synthesis and exhibited high solubility in organic solvents.

Development of a new N(π)-protecting group for histidine, N(π)-1- adamantyloxymethylhistidine

N(π)-1-adamantyloixymethylhistidine, His(N(π)-1-Adom) was prepared, and the properties of the 1-adom group were examined. 1-Adom group can be easily removed by TFA; it is stable to 20% piperidine/DMF and 1N NaOH. His(N(π+)- 1-Adom) derivatives can suppress recemization during coupling reaction. TRH was synthesized using His(N(π)-1Adom), successfully.

Facile Preparation of the 1-Hydroxybenzotriazolyl Ester of N-Tritylpyroglutamic Acid and its Application to the Synthesis of TRH, 2>TRH and Analogues Incorporating cis- and trans-4-Hydroxy-L-proline

One-pot treatment of N-trityl-L-glutamic acid with DCC followed by DCC-HOBt provided a high yielding synthesis of the 1-hydroxybenzotriazolyl ester of N-trityl-L-pyroglutamic acid (Trt-Glp). Coupling of this active ester with the methyl esters of Nim-tritylated L- and D-histidine provided the corresponding dipeptides which upon saponification and coupling with the methyl esters of L-proline and trans-4-hydroxy-L-proline (Hyp) gave the protected tripeptides Trt-Glp-L and D-His-(Nim-Trt)-Pro-OMe and Trt-Glp-L and D-His(Nim-Trt)-Hyp-OMe. Some 10percent of the epimeric (at the His residue) products were formed during this procedure. Sequential saponification and one-pot Mitsunobu-type intramolecular esterification of the latter tripeptides, followed by transesterification with MeOH, provided the corresponding tripeptides Trt-Glp-L and D-His(Nim-Trt)-cHyp-OMe with inversion of configuration at C-4 of the Hyp ring. The observed conformer ratios about the His-Pro amide for all of these tripeptides are discussed in terms of structural features. Detritylation with trifluoroacetic acid followed by ammonolysis completed the synthesis of TRH and its analogues Glp-D-His-Pro-NH2, Glp-L- and D-His-Hyp-NH2 and Glp-L- and -D-His-cHyp-NH2.