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Serotonin antagonist and reuptake inhibitor

Class of drug

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

List of SARIs

Marketed

Commercially available serotonin antagonist and reuptake inhibitors include etoperidone (Axiomin, Etonin), lorpiprazole (Normarex), mepiprazole (Psigodal), nefazodone, (Desyrel).

Never marketed

lubazodone (YM-992, YM-35995) – a SARI that, as of this date, had not come to market.

Miscellaneous

vilazodone (Viibryd) – a related drug not fitting into this class, as it acts solely as a 5-HT1A receptor partial agonist, but not as a serotonin antagonist; generally labeled as serotonin modulator and stimulator.
vortioxetine (Trintellix) – another closely related drug generally labeled as a serotonin modulator and stimulator.
niaprazine (Nopron) – a related drug that does not inhibit the reuptake of serotonin or other monoamines.
medifoxamine (Clédial, Gerdaxyl) – a serotonin–dopamine reuptake inhibitor and 5-HT2A and 5-HT2C receptor antagonist, although not grouped as such.

Pharmacology

Binding profiles

The binding profiles of SARIs and some metabolites in terms of their affinities (Ki, nM) for various receptors and transporters are as follows:

Compound	[5-HT1A](5-ht1a-receptor)	[5-HT2A](5-ht2a-receptor)	[5-HT2B](5-ht2b-receptor)	[5-HT2C](5-ht2c-receptor)	[5-HT3](5-ht3-receptor)	[5-HT6](5-ht6-receptor)	[5-HT7](5-ht7-receptor)	α1	α2	D2	H1
Etoperidone	890	20,000	52,000	85	36	ND	ND	ND	ND	ND	38
Hydroxynefazodone	165–1,203	376–1,053	ND	56–589	7.2–34	ND	ND	ND	ND	ND	8.0–145
	202–432	1,940–4,360	ND	44–400	32–398	3.2–63	3.4–251	427	1,748	163	97–2,900
Nefazodone	200–459	360–618	360	80	26	ND	72	ND	ND	ND	5.5–48
Trazodone	160–367	≥8,500	≥7,400	96–118	20–45	74–189	224–402	10,000	10,000	1,782	12–153
Triazoledione	≥34,527	100,000	ND	636–1,371	159–211	ND	ND	ND	ND	ND	173
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

These drugs act as antagonists or inverse agonists of the 5-HT2A, α1-adrenergic, and H1 receptors, as partial agonists of the 5-HT1A receptor, and as inhibitors of the transporters. mCPP is an antagonist of the 5-HT2B receptor, an agonist of the 5-HT1A, 5-HT2C, and 5-HT3 receptors, and acts as a partial agonist of the human 5-HT2A and 5-HT2C receptors.

References

(April 2025}} and [[trazodone]]{{cite book). "Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications". Cambridge University Press.
(2008). "Foye's Principles of Medicinal Chemistry". Lippincott Williams & Wilkins (Wolters Kluwer Health).
(1994). "The Pharmacokinetics and Pharmacodynamics of Medifoxamine After Oral Administration in Healthy Elderly Volunteers". Eur. J. Clin. Pharmacol..
"PDSP K_i Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.
(May 2005). "Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding". Journal of Psychopharmacology.
(1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Arch. Pharmacol..
(1996). "m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor". NeuroReport.
(November 1994). "m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine are partial agonists at cloned 5-HT2A receptors expressed in fibroblasts". The Journal of Pharmacology and Experimental Therapeutics.
(September 1999). "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". British Journal of Pharmacology.

Info: Wikipedia Source

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antidepressants anxiolytics serotonin-receptor-antagonists serotonin-reuptake-inhibitors

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