Biology:Montirelin
Montirelin (also known as CG-3703 or NS-3) is a synthetic analogue of thyrotropin-releasing hormone (TRH), designed to enhance central nervous system stimulation with greater potency and duration than natural TRH.[1]
Montirelin binds to TRH receptors in the brain, stimulating the release of thyrotropin (TSH) and prolactin. It exhibits sustained receptor occupancy and a counter-clockwise hysteresis between plasma concentration and receptor binding, suggesting prolonged CNS activity.
Montirelin has demonstrated efficacy in animal models for:[2][3]
- Concussion-induced unconsciousness
- Cerebral ischemia
- Memory disruption
- Narcolepsy and cataplexy
- Seizures and spontaneous convulsions
- Spinal trauma
In human studies, a 0.5 mg dose administered over 14 days improved consciousness in 73% of patients with neurological disturbances. Its ability to stimulate cholinergic and noradrenergic systems suggests promise in treating cognitive dysfunction and sleep disorders. Although it the patent, it said that the strength of the medicine was 4mg per tablet, but in contrast to TRH it can be administered orally and is more resistant to metabolic degradation.[1]
Synthesis
Synthesis:[4][5] Patent (Ex 10):[6] (CD)
The catalytic hydrogenation of (S)-1-N-Cbz-prolinamide [34079-31-7] (1) gives L-Prolinamide [7531-52-4] (2). This is condensed with Z-His-NHNH2 [49706-31-2] (3) in the presence of nitrous acid to give Benzyloxycarbonyl-L-histidyl-L-prolineamide, PC13229382[7] (4). The protecting group is hydrolyzed in acid to give His-pro-amide [33605-69-5] (5). This is finally condensed with (3R,6R)-6-Methyl-5-oxothiomorpholine-3-carboxylic acid, PC99645792[8] (6) in the presence of by of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, completing the synthesis of Montirelin (7).
Other TRH analogues
Analogues of TRH is not just limited to montirelin. Other agents to consider include the following:
- DN-1417 [77026-80-3]
- JTP 2942 [148152-77-6]
- RX-77368 [76820-40-1]
- Orotirelin [62305-86-6]
References
- ↑ 1.0 1.1 Kimura K, Ukai Y, Ogasawara T, Nakagawa Y, "Nootropic agent", US patent 4956364, issued 11 September 1990, assigned to Gruenenthal GmbH
- ↑ "Stimulation of locomotion in neonate rats by TRH analogue CG3703". Neuropeptides 26 (1): 71–5. January 1994. doi:10.1016/0143-4179(94)90096-5. PMID 8159287.
- ↑ "Permeability of NS-3, a thyrotropin-releasing hormone analogue, into the brain after its systemic administration in rats: a microdialysis study". The Journal of Pharmacy and Pharmacology 47 (10): 833–6. October 1995. doi:10.1111/j.2042-7158.1995.tb05750.x. PMID 8583352.
- ↑ "Synthesis of a series of residue 1 (pyroglutamic acid) analogs of thyrotrophin releasing hormone". International Journal of Peptide and Protein Research 14 (3): 216–26. 1979. doi:10.1111/j.1399-3011.1979.tb01928.x. PMID 118133.
- ↑ "CG-3703". Drugs of the Future 8 (12): 1007. 1983. doi:10.1358/dof.1983.008.12.75170. ISSN 0377-8282.
- ↑ Schwertner E, Herrling S, "Dipeptide derivatives, process for manufacture and pharmaceutical preparation", US patent 4045556, issued 10 August 1977-08
- ↑ "Benzyloxycarbonyl-L-histidyl-L-prolineamide". PubMed. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/13229382.
- ↑ "(3R,6R)-6-Methyl-5-oxothiomorpholine-3-carboxylic acid". PubMed. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/99645792.
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