Amesergide

Amesergide (INNTooltip International Nonproprietary Name, USANTooltip 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.^[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]

Amesergide

Clinical data
Other names	LY-237733; N-Cyclohexyl-11-isopropyllysergamide
Routes of administration	By mouth
Identifiers
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
CAS Number	121588-75-8
PubChem CID	9821951
ChemSpider	7997700
UNII	EJL329H95R
KEGG	D02893
ChEMBL	ChEMBL160293
CompTox Dashboard (EPA)	DTXSID8052851
Chemical and physical data
Formula	C25H35N3O
Molar mass	393.575 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)N1C=C2C[C@@H]3[C@H](C[C@H](CN3C)C(=O)NC4CCCCC4)C5=C2C1=CC=C5
InChI 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

Pharmacology

Pharmacodynamics

Amesergide acts as a selective antagonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors (K_i = 1.96–15.1 nM).^[4][5] It is also an antagonist of the serotonin 5-HT₇ receptor with relatively lower affinity (K_i = 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 (K_i = 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-HT_1D receptor (K_i = 57.9 nM) and lower affinity for the serotonin 5-HT_1A, α₁-adrenergic, and dopamine D₁ and D₂ receptors (K_i = 150–730 nM).^[4] It has negligible affinity for the histamine H₁ and muscarinic acetylcholine receptors (K_i > 10,000 nM).^[4] The drug does not appear to have been assessed at the serotonin 5-HT_1E, 5-HT_1F, 5-HT₄, 5-HT_5A, and 5-HT₆ receptors, nor at the dopamine D₃, D₄, and D₅ receptors.^[10]

Affinities of amesergide at various sites^[10]

Site	Affinity (Ki [nM])	Species	Source
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]
mAChTooltip Muscarinic acetylcholine receptor	>10,000	Rat	[4]
Notes: The smaller the affinity value, the more strongly the drug binds to the site.