Amesergide Explained
Amesergide (; 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.
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).[4] 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).[5] This profile of activity is similar to that of the so-called noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (Remeron).[6]
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.
Affinities of amesergide at various sites[7] | Site | Affinity (Ki [nM]) | Species | Source |
|---|
| 177.3 | Rat | [8] |
| ? | ? | ? |
| 57.9 | Cow | |
| 15.1
12.4 | Human
Rat | [9]
|
| 1.96 | Human | |
| 6.27
13.27 | Human
Pig |
|
| >10,000 | Rat | |
| ? | ? | ? |
| 78.0 | Human | [10] |
| 730 | Rat | |
| 50
13 | Rat |
[11] |
| >10,000 | Rat | |
| 150 | Rat | |
| 520 | Rat | |
| >10,000 | Rat | |
| >10,000 | Rat | |
| Notes: The smaller the affinity value, the more strongly the drug binds to the site. | |
External links
Notes and References
- Web site: Amesergide . AdisInsight . Springer Nature Switzerland AG .
- Book: William Andrew Publishing. Pharmaceutical Manufacturing Encyclopedia. 22 October 2013. Elsevier. 978-0-8155-1856-3. 239–.
- Book: Pertz HE, Eich EC . Ergot alkaloids and their derivatives as ligands for serotoninergic, dopaminergic, and adrenergic receptors. . Ergot: The Genus Claviceps. . Amsterdam . Harwood Academic Publishers . 1999 . 411–440 . 978-0-429-21976-4 . http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-%20The%20Genus%20Claviceps%20(1999)/TF3168ch14.pdf .
- Leopoldo M . Serotonin(7) receptors (5-HT(7)Rs) and their ligands . Current Medicinal Chemistry . 11 . 5 . 629–661 . March 2004 . 15032609 . 10.2174/0929867043455828 .
- Book: Feltner DE . New Molecules and New Therapies in Psychopharmacology . Hertzman M, Feltner DE . The Handbook of Psychopharmacology Trials: An Overview of Scientific, Political, and Ethical Concerns. https://books.google.com/books?id=Mn9lrAQ_nxUC&pg=PA390. June 1997. NYU Press. 978-0-8147-3532-9. 390–.
- Stimmel GL, Dopheide JA, Stahl SM . Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects . Pharmacotherapy . 17 . 1 . 10–21 . 1997 . 9017762 . 10.1002/j.1875-9114.1997.tb03674.x . 2020-08-28 . subscription . dead . 2454536 . https://web.archive.org/web/20210525180455/https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/j.1875-9114.1997.tb03674.x . 2021-05-25 .
- Web site: PDSP Ki Database . Psychoactive Drug Screening Program (PDSP). Bryan Roth . Roth BL, Driscol J . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 14 August 2017 .
- Foreman MM, Fuller RW, Nelson DL, Calligaro DO, Kurz KD, Misner JW, Garbrecht WL, Parli CJ . 6 . Preclinical studies on LY237733, a potent and selective serotonergic antagonist . The Journal of Pharmacology and Experimental Therapeutics . 260 . 1 . 51–57 . January 1992 . 1731051 .
- Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL . Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences . The Journal of Pharmacology and Experimental Therapeutics . 276 . 2 . 720–727 . February 1996 . 8632342 .
- Cushing DJ, Zgombick JM, Nelson DL, Cohen ML . 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 . June 1996 . 8667223 .
- Cohen ML, Kurz KD, Fuller RW, Calligaro DO . 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 . March 1994 . 8027933 . 10.1111/j.2042-7158.1994.tb03784.x . 36915233 .
