Amesergide
Chemical compound
From Wikipedia, the free encyclopedia
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 | Oral |
| Drug class | Serotonin receptor antagonist; Serotonin 5-HT2 receptor antagonist |
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| Formula | C25H35N3O |
| Molar mass | 393.575 g·mol−1 |
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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).[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]
| Site | Affinity (Ki [nM]) | Species | Source |
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| 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] |
| mACh | >10,000 | Rat | [4] |
| Notes: The smaller the affinity value, the more strongly the drug binds to the site. | |||
