amesergide
{{Short description|Chemical compound}}
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| 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
| image = Amesergide.svg
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| routes_of_administration = By mouth
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| CAS_number = 121588-75-8
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| PubChem = 9821951
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| ChemSpiderID = 7997700
| UNII = EJL329H95R
| KEGG = D02893
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| ChEMBL = 160293
| synonyms = LY-237733; N-Cyclohexyl-11-isopropyllysergamide
| C=25 | H=35 | N=3 | O=1
| SMILES = CC(C)N1C=C2C[C@@H]3[C@H](C[C@H](CN3C)C(=O)NC4CCCCC4)C5=C2C1=CC=C5
| StdInChI_Ref =
| StdInChI = 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
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| StdInChIKey = KEMOOQHMCGCZKH-JMUQELJHSA-N
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Amesergide ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|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.{{Cite web | url=http://adisinsight.springer.com/drugs/800001117 |title = Amesergide | work = AdisInsight | publisher = Springer Nature Switzerland AG }}{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA239|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=239–}}{{cite book | vauthors = Pertz HE, Eich EC | chapter = Ergot alkaloids and their derivatives as ligands for serotoninergic, dopaminergic, and adrenergic receptors. | title = Ergot: The Genus Claviceps. | location = Amsterdam | publisher = Harwood Academic Publishers | date = 1999 | pages = 411–440 | isbn = 978-0-429-21976-4 | chapter-url = http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-%20The%20Genus%20Claviceps%20(1999)/TF3168ch14.pdf }} It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.
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). It is also an antagonist of the serotonin 5-HT7 receptor with relatively lower affinity (Ki = 78.0 nM).{{cite journal | vauthors = Leopoldo M | title = Serotonin(7) receptors (5-HT(7)Rs) and their ligands | journal = Current Medicinal Chemistry | volume = 11 | issue = 5 | pages = 629–661 | date = March 2004 | pmid = 15032609 | doi = 10.2174/0929867043455828 }} 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).{{cite book | vauthors = Feltner DE | chapter = New Molecules and New Therapies in Psychopharmacology | veditors = Hertzman M, Feltner DE |title=The Handbook of Psychopharmacology Trials: An Overview of Scientific, Political, and Ethical Concerns| chapter-url=https://books.google.com/books?id=Mn9lrAQ_nxUC&pg=PA390|date=June 1997|publisher=NYU Press|isbn=978-0-8147-3532-9|pages=390–}} This profile of activity is similar to that of the so-called noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (Remeron).{{cite journal | vauthors = Stimmel GL, Dopheide JA, Stahl SM | title = Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects | journal = Pharmacotherapy | volume = 17 | issue = 1 | pages = 10–21 | year = 1997 | pmid = 9017762 | doi = 10.1002/j.1875-9114.1997.tb03674.x | url = https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x | access-date = 2020-08-28 | url-access = subscription | url-status = dead | s2cid = 2454536 | archive-url = https://web.archive.org/web/20210525180455/https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x | archive-date = 2021-05-25 }}
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). It has negligible affinity for the histamine H1 and muscarinic acetylcholine receptors (Ki > 10,000 nM). 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.
References
{{Reflist}}
External links
- {{Commonscatinline}}
- [http://adisinsight.springer.com/drugs/800001117 Amesergide - AdisInsight]
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{{Adrenergic receptor modulators}}
{{Dopamine receptor modulators}}
{{Serotonin receptor modulators}}
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{{Ergolines}}