# 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 α$_1$-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.

### 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:
| Compound | SERTTooltip Serotonin transporter | NETTooltip Norepinephrine transporter | DATTooltip Dopamine transporter | 5-HT$_{1A}$ | 5-HT$_{2A}$ | 5-HT$_{2B}$ | 5-HT$_{2C}$ | 5-HT$_3$ | 5-HT$_6$ | 5-HT$_7$ | α$_1$ | α$_2$ | D$_2$ | H$_1$ | 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 K$_i$ (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$_{2A}$, α$_1$-adrenergic, and H$_1$ receptors, as partial agonists of the 5-HT$_{1A}$ receptor, 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-HT$_3$ receptors, and acts as a partial agonist of the human 5-HT$_{2A}$ and 5-HT$_{2C}$ receptors.