Amesergide
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]
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Other names | LY-237733; N-Cyclohexyl-11-isopropyllysergamide |
Routes of administration | By mouth |
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Chemical and physical data | |
Formula | C25H35N3O |
Molar mass | 393.575 g·mol−1 |
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Pharmacology
Pharmacodynamics
Site | Ki (nM) | Species | Ref |
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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
- "Amesergide - AdisInsight".
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 239–. ISBN 978-0-8155-1856-3.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.1111/j.2042-7158.1994.tb03784.x. PMID 8027933. S2CID 36915233.
- Leopoldo M (2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Curr. Med. Chem. 11 (5): 629–61. doi:10.2174/0929867043455828. PMID 15032609.
- 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.
- 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.
External links
- Media related to Amesergide at Wikimedia Commons
- Amesergide - AdisInsight