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Amesergide

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
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
PubChemCID
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 nameLY-237733) is aserotonin receptor antagonist of theergoline andlysergamide families related tomethysergide which was under development byEli Lilly and Company for the treatment of a variety of conditions includingdepression,anxiety,schizophrenia,male sexual dysfunction,migraine, andthrombosis but was never marketed.[1][2][3] It reachedphase IIclinical trials for the treatment of depression,erectile dysfunction, andpremature ejaculation prior to the discontinuation of its development.[1]

Pharmacology

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Pharmacodynamics

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Amesergide acts as aselectiveantagonist of theserotonin5-HT2A,5-HT2B, and5-HT2C receptors (Ki = 1.96–15.1 nM).[4][5] It is also an antagonist of the serotonin5-HT7 receptor with relatively loweraffinity (Ki = 78.0 nM).[6] The drug is apotent antagonist of theα2-adrenergic receptor in addition to the5-HT2 receptors via its majoractive metabolite 4-hydroxyamesergide (Ki = 13 nM).[7][8] This profile of activity is similar to that of the so-callednoradrenergic and specific serotonergic antidepressant (NaSSA)mirtazapine (Remeron).[9]

Amesergide also has affinity for the serotonin5-HT1D receptor (Ki = 57.9 nM) and lower affinity for the serotonin5-HT1A,α1-adrenergic, anddopamineD1 andD2 receptors (Ki = 150–730 nM).[4] It has negligible affinity for thehistamineH1 andmuscarinic acetylcholine receptors (Ki > 10,000 nM).[4] The drug does not appear to have been assessed at the serotonin5-HT1E,5-HT1F,5-HT4,5-HT5A, and5-HT6 receptors, nor at the dopamineD3,D4, andD5 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]
mAChTooltip Muscarinic acetylcholine receptor>10,000Rat[4]
Notes: The smaller the affinity value, the more strongly the drug binds to the site.

References

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  1. ^ab"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. ^abcdefghijklmnoForeman 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. ^abcdWainscott 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. ^abCohen 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 fromthe original on 2021-05-25. Retrieved2020-08-28.
  10. ^abRoth 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. Retrieved14 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.

External links

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α1
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α2
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β
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D2-like
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5-HT1
5-HT1A
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5-HT2A
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5-HT2C
5-HT3–7
5-HT3
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5-HT5A
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Ergolines
(incl.lysergines)
Clavines
(6,8-dimethylergolines)
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(lysergic acid amides)
Ergopeptines
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Partial ergolines
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