Amesergide (, ; developmental code name LY-237733) is a

serotonin receptor antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action at serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A receptor are sometimes used as atypical antipsychotics (contrast wi ...

of the

ergoline Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of the ...

and

lysergamide Amides of lysergic acid are collectively known as lysergamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors. See also * Ergoline * Bromocriptine * Fumigaclavi ...

families related to methysergide which was under development by

Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colon ...

for the treatment of a variety of conditions including depression,

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schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

, male sexual dysfunction,

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, and

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thr ...

but was never marketed.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. It reached phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for the treatment of depression,

erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of ma ...

, and

premature ejaculation Premature ejaculation (PE) occurs when a man expels semen (and most likely experiences orgasm) soon after beginning sexual activity, and with minimal penile stimulation. It has also been called ''early ejaculation'', ''rapid ejaculation'', '' ...

prior to the discontinuation of its development.

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). It is also an antagonist of the serotonin 5-HT₇ receptor with relatively lower

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(K_i = 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 An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

4-hydroxyamesergide (K_i = 13 nM). This profile of activity is similar to that of the so-called

noradrenergic and specific serotonergic antidepressant Noradrenergic and specific serotonergic antidepressants (NaSSAs) are a class of psychiatric drugs used primarily as antidepressants. They act by antagonizing the α2-adrenergic receptor and certain serotonin receptors such as 5-HT2A and 5-HT2 ...

(NaSSA)

mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is ...

(Remeron). 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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

D₁ and D₂ receptors (K_i = 150–730 nM). It has negligible affinity for the

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

H₁ and

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several r ...

s (K_i > 10,000 nM). 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.

References

External links

*
Amesergide - AdisInsight
{{Ergolines 5-HT2A antagonists 5-HT2B antagonists 5-HT2C antagonists 5-HT7 antagonists Abandoned drugs Alpha-2 blockers Antidepressants Anxiolytics Isopropyl compounds Lysergamides