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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