Amesergide

Amesergide
Clinical data
Other namesLY-237733; N-Cyclohexyl-11-isopropyllysergamide
Routes of
administration		By mouth
Identifiers
IUPAC name
  • (6aR,9R,10aR)-N-Cyclohexyl-7-methyl-4-propan-2-yl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H35N3O
Molar mass393.575 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)N1C=C2C[C@@H]3[C@H](C[C@H](CN3C)C(=O)NC4CCCCC4)C5=C2C1=CC=C5
InChI
  • InChI=1S/C25H35N3O/c1-16(2)28-15-17-13-23-21(20-10-7-11-22(28)24(17)20)12-18(14-27(23)3)25(29)26-19-8-5-4-6-9-19/h7,10-11,15-16,18-19,21,23H,4-6,8-9,12-14H2,1-3H3,(H,26,29)/t18-,21-,23-/m1/s1
  • Key:KEMOOQHMCGCZKH-JMUQELJHSA-N

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]

Affinities of amesergide at various sites[10]
SiteAffinity (Ki [nM])SpeciesSource
5-HT1A177.3Rat[4]
5-HT1B ? ? ?
5-HT1D57.9Cow[4]
5-HT2A15.1
12.4		Human
Rat		[5]
[4]
5-HT2B1.96Human[5]
5-HT2C6.27
13.27		Human
Pig		[5]
[4]
5-HT3>10,000Rat[4]
5-HT6 ? ? ?
5-HT778.0Human[11]
α1730Rat[4]
α250
13 (MB)		Rat[4]
[7]
β>10,000Rat[4]
D1150Rat[4]
D2520Rat[4]
H1>10,000Rat[4]
mACh>10,000Rat[4]
Notes: The smaller the affinity value, the more strongly the drug binds to the site.

References

  1. 1 2 "Amesergide - AdisInsight".
  2. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 239–. ISBN 978-0-8155-1856-3.
  3. ↑ Pertz, H. E. I. N. Z., & Eich, E. C. K. A. R. T. (1999). Ergot alkaloids and their derivatives as ligands for serotoninergic, dopaminergic, and adrenergic receptors. Ergot: the genus Claviceps. Harwood Academic Publishers, Amsterdam, The Netherlands, 411-440.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Foreman MM, Fuller RW, Nelson DL, Calligaro DO, Kurz KD, Misner JW, Garbrecht WL, Parli CJ (1992). "Preclinical studies on LY237733, a potent and selective serotonergic antagonist". J. Pharmacol. Exp. Ther. 260 (1): 51–7. PMID 1731051.
  5. 1 2 3 4 Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL (1996). "Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences". J. Pharmacol. Exp. Ther. 276 (2): 720–7. PMID 8632342.
  6. ↑ Leopoldo M (2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Curr. Med. Chem. 11 (5): 629–61. doi:10.2174/0929867043455828. PMID 15032609.
  7. 1 2 Cohen ML, Kurz KD, Fuller RW, Calligaro DO (1994). "Comparative 5-HT2-receptor antagonist activity of amesergide and its active metabolite 4-hydroxyamesergide in rats and rabbits". J. Pharm. Pharmacol. 46 (3): 226–9. doi:10.1111/j.2042-7158.1994.tb03784.x. PMID 8027933. S2CID 36915233.
  8. ↑ Marc Hertzman; Douglas E. Feltner (June 1997). The Handbook of Psychopharmacology Trials: An Overview of Scientific, Political, and Ethical Concerns. NYU Press. pp. 390–. ISBN 978-0-8147-3532-9.
  9. ↑ Stimmel GL, Dopheide JA, Stahl SM (1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy. 17 (1): 10–21. doi:10.1002/j.1875-9114.1997.tb03674.x. PMID 9017762. S2CID 2454536.
  10. 1 2 Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  11. ↑ Cushing DJ, Zgombick JM, Nelson DL, Cohen ML (1996). "LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery". J. Pharmacol. Exp. Ther. 277 (3): 1560–6. PMID 8667223.
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