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Abandoned drugs
Amesergide
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Amesergide

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Amesergide
Amesergide.svg
Clinical data
Other names LY-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
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H35N3O
Molar mass 393.575 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 (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. 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). 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). This profile of activity is similar to that of the so-called noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine (Remeron).

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
Site Affinity (Ki [nM]) Species Source
5-HT1A 177.3 Rat
5-HT1B ? ? ?
5-HT1D 57.9 Cow
5-HT2A 15.1
12.4		 Human
Rat
5-HT2B 1.96 Human
5-HT2C 6.27
13.27		 Human
Pig
5-HT3 >10,000 Rat
5-HT6 ? ? ?
5-HT7 78.0 Human
α1 730 Rat
α2 50
13 (MB)		 Rat
β >10,000 Rat
D1 150 Rat
D2 520 Rat
H1 >10,000 Rat
mACh >10,000 Rat
Notes: The smaller the affinity value, the more strongly the drug binds to the site.

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