Chemistry:Serotonin antagonist and reuptake inhibitor

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Short description: Class of drug
Chemical structure of the serotonin antagonist and reuptake inhibitor trazodone.

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

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-HT1A 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-HT2A and 5-HT2C 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 (Ki, nM) for various receptors and transporters are as follows:[2]

Compound SERT NET DAT 5-HT1A 5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT6 5-HT7 α1 α2 D2 H1 mACh
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
mCPP 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-HT2A, α1-adrenergic, and H1 receptors, as partial agonists of the 5-HT1A receptor,[3] and as inhibitors of the transporters. mCPP is an antagonist of the 5-HT2B receptor, an agonist of the 5-HT1A,[3] 5-HT2C, and 5-HT3 receptors,[4][5] and acts as a partial agonist of the human 5-HT2A[6] and 5-HT2C receptors.[7]

See also

References

  1. ↑ "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". Eur. J. Clin. Pharmacol. 46 (2): 163–6. 1994. doi:10.1007/bf00199882. PMID 8039537. 
  2. ↑ "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. https://pdsp.unc.edu/databases/kidb.php. 
  3. ↑ 3.0 3.1 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. 
  4. ↑ "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn Schmiedebergs Arch. Pharmacol. 359 (1): 1–6. 1999. doi:10.1007/pl00005315. PMID 9933142. 
  5. ↑ "m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor". NeuroReport 7 (9): 1457–60. 1996. 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. https://pubmed.ncbi.nlm.nih.gov/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. PMID 10498829. 



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