Serotonin antagonist and reuptake inhibitor

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-HT_2A 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.

Chemical structure of the serotonin antagonist and reuptake inhibitor trazodone.

List of SARIs

Marketed

• Etoperidone (Axiomin, Etonin)
• Lorpiprazole (Normarex)
• Mepiprazole (Psigodal)
• Nefazodone (Serzone, Nefadar)
• Trazodone (Desyrel)

Miscellaneous

• Vilazodone (Viibryd) – a related drug but does not fit into this class as it does not function as a serotonin antagonist, acting solely as a 5-HT_1A receptor partial agonist instead.
• Vortioxetine (Trintellix) – another closely related drug, could technically be considered to be a member of this group, but both vilazodone and vortioxetine are instead generally labeled as serotonin modulators and stimulators.
• Niaprazine (Nopron) – a drug related to this group but does not inhibit the reuptake of serotonin or the other monoamines.
• Medifoxamine (Clédial, Gerdaxyl) – could perhaps technically be said to belong to this group, as it is a serotonin–dopamine reuptake inhibitor and 5-HT_2A and 5-HT_2C receptor antagonist, but not grouped as such.^[1]

Never marketed

• Lubazodone (YM-992, YM-35995) – a SARI that was never marketed.

Pharmacology

Binding profiles

The binding profiles of SARIs and some metabolites in terms of their affinities (K_i, nM) for various receptors and transporters are as follows:^[2]

Compound	SERTTooltip Serotonin transporter	NETTooltip Norepinephrine transporter	DATTooltip Dopamine transporter	5-HT1A	5-HT2A	5-HT2B	5-HT2C	5-HT3	5-HT6	5-HT7	α1	α2	D2	H1	mAChTooltip Muscarinic acetylcholine receptor
Etoperidone	890	20,000	52,000	85	36	ND	ND	ND	ND	ND	38	570	2,300	3,100	>35,000
Hydroxynefazodone	165–1,203	376–1,053	ND	56–589	7.2–34	ND	ND	ND	ND	ND	8.0–145	63–2,490	ND	ND	11,357
mCPPTooltip meta-Chlorophenylpiperazine	202–432	1,940–4,360	ND	44–400	32–398	3.2–63	3.4–251	427	1,748	163	97–2,900	106–570	>10,000	326	>10,000
Nefazodone	200–459	360–618	360	80	26	ND	72	ND	ND	ND	5.5–48	84–640	910	≥370	>10,000
Trazodone	160–367	≥8,500	≥7,400	96–118	20–45	74–189	224–402	>10,000	>10,000	1,782	12–153	106–728	≥3,500	220–1,100	>10,000
Triazoledione	≥34,527	>100,000	ND	636–1,371	159–211	ND	ND	ND	ND	ND	173	1,915	ND	ND	>100,000
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-HT_2A, α₁-adrenergic, and H₁ receptors, as partial agonists of the 5-HT_1A receptor,^[3] and as inhibitors of the transporters. mCPP is an antagonist of the 5-HT_2B receptor, an agonist of the 5-HT_1A,^[3] 5-HT_2C, and 5-HT₃ receptors,^[4][5] and acts as a partial agonist of the human 5-HT_2A^[6] and 5-HT_2C receptors.^[7]

See also

• List of antidepressants
• Serotonin modulator and stimulator (SMS)
• Noradrenergic and specific serotonergic antidepressant (NaSSA)
• Norepinephrine-dopamine disinhibitor (NDDI)
• Selective serotonin reuptake inhibitor (SSRI)

References

1. Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH (1994). "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". Eur. J. Clin. Pharmacol. 46 (2): 163–6. doi:10.1007/bf00199882. PMID 8039537. S2CID 6978939.
2. Roth, BL; Driscol, J. "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 11 September 2017.
3. Odagaki Y; Toyoshima R; Yamauchi T (May 2005). "Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding". Journal of Psychopharmacology. 19 (3): 235–41. doi:10.1177/0269881105051526. PMID 15888508. S2CID 27389008.
4. Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Arch. Pharmacol. 359 (1): 1–6. doi:10.1007/pl00005315. PMID 9933142. S2CID 20150858.
5. Thomas DR, Gager TL, Holland V, Brown AM, Wood MD (1996). "m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor". NeuroReport. 7 (9): 1457–60. doi:10.1097/00001756-199606170-00002. PMID 8856697.
6. Grotewiel, M. S.; Chu, H.; Sanders-Bush, E. (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. 271 (2): 1122–1126. PMID 7965773. Retrieved 2022-10-02.
7. Porter, R. H.; Benwell, K. R.; Lamb, H.; Malcolm, C. S.; Allen, N. H.; Revell, D. F.; Adams, D. R.; Sheardown, M. J. (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. 128 (1): 13–20. doi:10.1038/sj.bjp.0702751. ISSN 0007-1188. PMC 1571597. PMID 10498829.