Serotonin antagonist and reuptake inhibitor explained

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.

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 for various receptors and transporters are as follows:^[2]

! Compound !! !! !! !! 5-HT_1A !! 5-HT_2A !! 5-HT_2B !! 5-HT_2C !! 5-HT₃ !! 5-HT₆ !! 5-HT₇ !! α₁ !! α₂ !! D₂ !!H₁ !!

890

20,000

52,000

85

36

38

570

2,300

3,100

>35,000

165–1,203

376–1,053

56–589

7.2–34

8.0–145

63–2,490

11,357

202–432

1,940–4,360

44–400

32–398

3.2–63

3.4–251

427

1,748

163

97–2,900

106–570

>10,000

326

>10,000

200–459

360–618

360

80

26

72

5.5–48

84–640

910

≥370

>10,000

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

≥34,527

>100,000

636–1,371

159–211

173

1,915

>100,000

Values are . 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, 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)

Notes and References

1. Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH . The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers . Eur. J. Clin. Pharmacol. . 46 . 2 . 163–6 . 1994 . 8039537 . 10.1007/bf00199882. 6978939 .
2. Web site: PDSP K_i Database . Psychoactive Drug Screening Program (PDSP). Bryan Roth . Roth, BL . Driscol, J . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 11 September 2017 .
3. Odagaki Y . Toyoshima R . Yamauchi T . 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 . May 2005 . 15888508 . 10.1177/0269881105051526 . 27389008 .
4. Nelson DL, Lucaites VL, Wainscott DB, Glennon RA . 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 . 1999 . 9933142 . 10.1007/pl00005315. 20150858 .
5. Thomas DR, Gager TL, Holland V, Brown AM, Wood MD . m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor . NeuroReport . 7 . 9 . 1457–60 . 1996 . 8856697 . 10.1097/00001756-199606170-00002.
6. Grotewiel . M. S. . Chu . H. . Sanders-Bush . E. . m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine are partial agonists at cloned 5-HT2A receptors expressed in fibroblasts . The Journal of Pharmacology and Experimental Therapeutics . November 1994 . 271 . 2 . 1122–1126 . 7965773 . 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. 10.1038/sj.bjp.0702751. 0007-1188. 1571597. 10498829.