Amesergide

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Amesergide
Amesergide.svg
Clinical data
SynonymsLY-237733; N-Cyclohexyl-11-isopropyllysergamide
Routes of
administration
By mouth
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H35N3O
Molar mass393.575 g/mol 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[edit]

Pharmacodynamics[edit]

Amesergide[4]
Site Ki (nM) Species Ref
5-HT1A 177.3 Rat [5]
5-HT1B ND ND ND
5-HT1D 57.9 Cow [5]
5-HT2A 15.1
12.4
Human
Rat
[6]
[5]
5-HT2B 1.96 Human [6]
5-HT2C 6.27
13.27
Human
Pig
[6]
[5]
5-HT3 >10,000 Rat [5]
5-HT6 ND ND ND
5-HT7 78.0 Human [7]
α1 730 Rat [5]
α2 50
13 (MB)
Rat [5]
[8]
β >10,000 Rat [5]
D1 150 Rat [5]
D2 520 Rat [5]
H1 >10,000 Rat [5]
mACh >10,000 Rat [5]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Amesergide acts as a selective antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors (Ki = 1.96–15.1 nM).[5][6] It is also an antagonist of the serotonin 5-HT7 receptor with relatively lower affinity (Ki = 78.0 nM).[9] 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).[8][10] This profile of activity is similar to that of the so-called noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (Remeron).[11]

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).[5] It has negligible affinity for the histamine H1 and muscarinic acetylcholine receptors (Ki > 10,000 nM).[5] 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.[4]

References[edit]

  1. ^ a b 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.
  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. ^ a b Roth, BL; Driscol, J. "PDSP Ki Database" (HTML). 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.
  5. ^ a b c d e f g h i j k l m n o 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.
  6. ^ a b c d 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.
  7. ^ 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.
  8. ^ a b 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. PMID 8027933.
  9. ^ Leopoldo M (2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Curr. Med. Chem. 11 (5): 629–61. PMID 15032609.
  10. ^ 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.
  11. ^ Stimmel GL, Dopheide JA, Stahl SM (1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy. 17 (1): 10–21. PMID 9017762.

External links[edit]