Chemistry:Amesergide

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Short description: Chemical compound
Amesergide
Amesergide.svg
Clinical data
Other namesLY-237733; N-Cyclohexyl-11-isopropyllysergamide
Routes of
administration		By mouth
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC25H35N3O
Molar mass393.575 g·mol−1
3D model (JSmol)

Amesergide (INN, USAN; developmental code name LY-237733) is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed.[1][2][3] It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.[1]

Pharmacology

Pharmacodynamics

Amesergide acts as a selective antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors (Ki = 1.96–15.1 nM).[4][5] It is also an antagonist of the serotonin 5-HT7 receptor with relatively lower affinity (Ki = 78.0 nM).[6] The drug is a potent antagonist of the α2-adrenergic receptor in addition to the 5-HT2 receptors via its major active metabolite 4-hydroxyamesergide (Ki = 13 nM).[7][8] This profile of activity is similar to that of the so-called noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (Remeron).[9]

Amesergide also has affinity for the serotonin 5-HT1D receptor (Ki = 57.9 nM) and lower affinity for the serotonin 5-HT1A, α1-adrenergic, and dopamine D1 and D2 receptors (Ki = 150–730 nM).[4] It has negligible affinity for the histamine H1 and muscarinic acetylcholine receptors (Ki > 10,000 nM).[4] The drug does not appear to have been assessed at the serotonin 5-HT1E, 5-HT1F, 5-HT4, 5-HT5A, and 5-HT6 receptors, nor at the dopamine D3, D4, and D5 receptors.[10]

Site Affinity (Ki [nM]) Species Source
5-HT1A 177.3 Rat [4]
5-HT1B ? ? ?
5-HT1D 57.9 Cow [4]
5-HT2A 15.1
12.4		 Human
Rat		 [5]
[4]
5-HT2B 1.96 Human [5]
5-HT2C 6.27
13.27		 Human
Pig		 [5]
[4]
5-HT3 >10,000 Rat [4]
5-HT6 ? ? ?
5-HT7 78.0 Human [11]
α1 730 Rat [4]
α2 50
13 (MB)		 Rat [4]
[7]
β >10,000 Rat [4]
D1 150 Rat [4]
D2 520 Rat [4]
H1 >10,000 Rat [4]
mACh >10,000 Rat [4]
Notes: The smaller the affinity value, the more strongly the drug binds to the site.

References

  1. ↑ 1.0 1.1 "Amesergide". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800001117. 
  2. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 239–. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA239. 
  3. ↑ "Ergot alkaloids and their derivatives as ligands for serotoninergic, dopaminergic, and adrenergic receptors.". Ergot: The Genus Claviceps.. Amsterdam: Harwood Academic Publishers. 1999. pp. 411–440. ISBN 978-0-429-21976-4. http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-%20The%20Genus%20Claviceps%20(1999)/TF3168ch14.pdf. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 "Preclinical studies on LY237733, a potent and selective serotonergic antagonist". The Journal of Pharmacology and Experimental Therapeutics 260 (1): 51–57. January 1992. PMID 1731051. 
  5. ↑ 5.0 5.1 5.2 5.3 "Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences". The Journal of Pharmacology and Experimental Therapeutics 276 (2): 720–727. February 1996. PMID 8632342. 
  6. ↑ "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Current Medicinal Chemistry 11 (5): 629–661. March 2004. doi:10.2174/0929867043455828. PMID 15032609. 
  7. ↑ 7.0 7.1 "Comparative 5-HT2-receptor antagonist activity of amesergide and its active metabolite 4-hydroxyamesergide in rats and rabbits". The Journal of Pharmacy and Pharmacology 46 (3): 226–229. March 1994. doi:10.1111/j.2042-7158.1994.tb03784.x. PMID 8027933. 
  8. ↑ "New Molecules and New Therapies in Psychopharmacology". The Handbook of Psychopharmacology Trials: An Overview of Scientific, Political, and Ethical Concerns. NYU Press. June 1997. pp. 390–. ISBN 978-0-8147-3532-9. https://books.google.com/books?id=Mn9lrAQ_nxUC&pg=PA390. 
  9. ↑ "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy 17 (1): 10–21. 1997. doi:10.1002/j.1875-9114.1997.tb03674.x. PMID 9017762. https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x. Retrieved 2020-08-28. 
  10. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  11. ↑ "LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery". The Journal of Pharmacology and Experimental Therapeutics 277 (3): 1560–1566. June 1996. PMID 8667223. 

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