Amesergide

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Amesergide
Clinical data
Other namesLY-237733; N-Cyclohexyl-11-isopropyllysergamide
Routes of
administration		By mouth
Identifiers
  • (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)
  • CC(C)N1C=C2C[C@@H]3[C@H](C[C@H](CN3C)C(=O)NC4CCCCC4)C5=C2C1=CC=C5
  • 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 (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name; 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

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Pharmacodynamics

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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]
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]
mAChTooltip Muscarinic acetylcholine receptor >10,000 Rat [4]
Notes: The smaller the affinity value, the more strongly the drug binds to the site.

References

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  1. ^ a b "Amesergide". AdisInsight. Springer Nature Switzerland AG.
  2. ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 239–. ISBN 978-0-8155-1856-3.
  3. ^ Pertz HE, Eich EC (1999). "Ergot alkaloids and their derivatives as ligands for serotoninergic, dopaminergic, and adrenergic receptors." (PDF). Ergot: The Genus Claviceps. Amsterdam: Harwood Academic Publishers. pp. 411–440. ISBN 978-0-429-21976-4.
  4. ^ 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, et al. (January 1992). "Preclinical studies on LY237733, a potent and selective serotonergic antagonist". The Journal of Pharmacology and Experimental Therapeutics. 260 (1): 51–57. PMID 1731051.
  5. ^ a b c d Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL (February 1996). "Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences". The Journal of Pharmacology and Experimental Therapeutics. 276 (2): 720–727. PMID 8632342.
  6. ^ Leopoldo M (March 2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Current Medicinal Chemistry. 11 (5): 629–661. doi:10.2174/0929867043455828. PMID 15032609.
  7. ^ a b Cohen ML, Kurz KD, Fuller RW, Calligaro DO (March 1994). "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. doi:10.1111/j.2042-7158.1994.tb03784.x. PMID 8027933. S2CID 36915233.
  8. ^ Feltner DE (June 1997). "New Molecules and New Therapies in Psychopharmacology". In Hertzman M, Feltner DE (eds.). 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. Archived from the original on 2021-05-25. Retrieved 2020-08-28.
  10. ^ a b 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 (June 1996). "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. PMID 8667223.
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