Serotonin receptor agonist

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The neurotransmitter serotonin (illustration) has various receptors.

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

Non-selective agonists[edit]

Serotonergic psychedelics such as tryptamines (e.g., psilocybin, psilocin, DMTTooltip dimethyltryptamine, 5-MeO-DMT, bufotenin), lysergamides (e.g., LSDTooltip lysergic acid diethylamide, ergine (LSA)), phenethylamines (e.g., mescaline, 2C-B, 25I-NBOMe), and amphetamines (e.g., MDATooltip 3,4-methylenedioxyamphetamine, DOMTooltip 2,5-dimethoxy-4-methylamphetamine) are non-selective agonists of serotonin receptors. Their hallucinogenic effects are specifically mediated by activation of the 5-HT2A receptor.

Drugs that increase extracellular serotonin levels such as serotonin reuptake inhibitors (e.g., fluoxetine, venlafaxine), serotonin releasing agents (e.g., fenfluramine, MDMATooltip methylenedioxymethamphetamine), and monoamine oxidase inhibitors (e.g., phenelzine, moclobemide) are indirect non-selective serotonin receptor agonists. They are used variously as antidepressants, anxiolytics, antiobsessionals, appetite suppressants, and entactogens.

5-HT1 receptor agonists[edit]

5-HT1A receptor agonists[edit]

Azapirones such as buspirone, gepirone, and tandospirone are 5-HT1A receptor partial agonists marketed primarily as anxiolytics, but also as antidepressants. The antidepressants vilazodone and vortioxetine are 5-HT1A receptor partial agonists. Flibanserin, a drug used for female sexual dysfunction, is a 5-HT1A receptor partial agonist. Many atypical antipsychotics, such as aripiprazole, asenapine, clozapine, lurasidone, quetiapine, and ziprasidone, are 5-HT1A receptor partial agonists, and this action is thought to contribute to their beneficial effects on negative symptoms in schizophrenia.

5-HT1B receptor agonists[edit]

Triptans such as sumatriptan, rizatriptan, and naratriptan are 5-HT1B receptor agonists that are used to abort migraine and cluster headache attacks. The ergoline antimigraine agent ergotamine also acts on this receptor.

Serenics such as batoprazine, eltoprazine, and fluprazine are agonists of the 5-HT1B receptor and other serotonin receptors, and have been found to produce antiaggressive effects in animals, but have not been marketed. Eltoprazine is under development for the treatment of aggression and for other indications.[1]

5-HT1D receptor agonists[edit]

In addition to being 5-HT1B agonists, triptans (i.e. sumatriptan, almotriptan, zolmitriptan, naratriptan, eletriptan, frovatriptan and rizatriptan) are also agonists at the 5-HT1D receptor, which contributes to their antimigraine effect caused by vasoconstriction of blood vessels in the brain. The same is true for ergotamine.

5-HT1E receptor agonists[edit]

The triptan eletriptan is an agonist of the 5-HT1E receptor. BRL-54443 is a selective 5-HT1E and 5-HT1F receptor agonist which is used in scientific research.

5-HT1F receptor agonists[edit]

Triptans such as eletriptan, naratriptan, and sumatriptan are agonists of the 5-HT1F receptor. Lasmiditan is a selective 5-HT1F agonist that is under development by Eli Lilly and Company for the treatment of migraine.[2][3]

5-HT2 receptor agonists[edit]

5-HT2A receptor agonists[edit]

Serotonergic psychedelics like psilocybin, LSD, and mescaline act as 5-HT2A receptor agonists. Their actions at this receptor are thought to be responsible for their hallucinogenic effects. Most of these drugs also act as agonists of other serotonin receptors. Not all 5-HT2A receptor agonists are psychoactive.[4]

The 25-NB (NBOMe) series is a family of phenethylamine serotonergic psychedelics that, unlike other classes of serotonergic psychedelics, act as highly selective 5-HT2A receptor agonists.[5] The most well-known member of the 25-NB series is 25I-NBOMe.[6][7] (2S,6S)-DMBMPP is an analogue of the 25-NB compounds and is the most highly selective agonist of the 5-HT2A receptor that has been identified to date.[8] O-4310 (1-isopropyl-6-fluoropsilocin) is a tryptamine derivative that is a highly selective agonist of the 5-HT2A receptor.[9]

Selective 5-HT2A receptor agonists like the 25-NB compounds, specifically those which can behave as full agonists at this receptor, can cause serotonin syndrome-like adverse effects such as hyperthermia, hyperpyrexia, tachycardia, hypertension, clonus, seizures, agitation, aggression, and hallucinations which has ended in death on numerous occasions despite these particular drugs only being available to drug users for about 2–3 years, being widely in use mostly in the period from 2010-2012. Bans were put in place around 2012-2013 by countries where they had risen to popularity. They quickly and often accidentally lead to overdose.[7][10] In contrast to the aforementioned drugs's potent, selective, and most importantly, full agonism (meaning the drug can fully activate the receptor to 100% of its activation potential, and does so even with minuscule amounts due to high potency, LSD, like the other "safe" psychedelics which are almost impossible to overdose fatally on, is a partial agonist, and this means it has a limit of how much it can activate the receptor, a limit which is basically impossible to exceed even with exponentially larger amounts of the drug. These partial agonists have proven relatively safe after having seen widespread abuse by drug users for many decades.[10] Activation of the 5-HT2A receptor is also implicated in serotonin syndrome caused by indirect serotonin receptor agonists like serotonin reuptake inhibitors, serotonin releasing agents, and monoamine oxidase inhibitors.[10][11] Antagonists of the 5-HT2A receptor like cyproheptadine and chlorpromazine are able to reverse and mediate recovery from serotonin syndrome.[12]

5-HT2B receptor agonists[edit]

Agonists of the 5-HT2B receptor are implicated in the development of cardiac fibrosis.[13] Fenfluramine, pergolide, and cabergoline have been withdrawn from some markets for this reason.[14] Many serotonergic psychedelics, such as LSD and psilocin, have been shown to activate this receptor directly.[15] MDMA has been reported to be both a potent direct agonist[13] and have an indirect effect by increasing plasma serotonin levels.[16]

5-HT2C receptor agonists[edit]

Lorcaserin is an appetite suppressant and anti-obesity drug which acts as a selective 5-HT2C receptor agonist. meta-Chlorophenylpiperazine (mCPP) is a 5-HT2C-preferring serotonin receptor agonist that induces anxiety and depression and can cause panic attacks in susceptible individuals.

5-HT3 receptor agonists[edit]

2-Methyl-5-hydroxytryptamine (2-methylserotonin) and quipazine are moderately selective agonists of the 5-HT3 receptor that are used in scientific research. Agonists of this receptor are known to induce nausea and vomiting, and are not used medically.

5-HT4 receptor agonists[edit]

Cisapride and tegaserod are 5-HT4 receptor partial agonists that were used to treat disorders of gastrointestinal motility. Prucalopride is a highly selective 5-HT4 receptor agonist that can be used to treat certain disorders of gastrointestinal motility. Other 5-HT4 receptor agonists have shown potential to be nootropic and antidepressant drugs, but have not been marketed for such indications.

5-HT5A receptor agonists[edit]

Valerenic acid, a constituent of valerian root, has been found to act as a 5-HT5A receptor agonist, and this action could be involved in the sleep-promoting effects of valerian.

5-HT6 receptor agonists[edit]

No selective agonists of the 5-HT6 receptor have been approved for medical use. Selective 5-HT6 receptor agonists like E-6801, E-6837, EMDT, WAY-181,187, and WAY-208,466 show antidepressant, anxiolytic, antiobsessional, and appetite suppressant effects in animals, but also impair cognition and memory.[17]

5-HT7 receptor agonists[edit]

AS-19 is a 5-HT7 receptor agonist that has been used in scientific research.

See also[edit]


  1. ^ "Eltoprazine - Elto Pharma - AdisInsight".
  2. ^ Capi M, de Andrés F, Lionetto L, Gentile G, Cipolla F, Negro A, Borro M, Martelletti P, Curto M (2017). "Lasmiditan for the treatment of migraine". Expert Opin Investig Drugs. 26 (2): 227–234. doi:10.1080/13543784.2017.1280457. PMID 28076702. S2CID 6034372.
  3. ^ "Lasmiditan - Eli Lilly and Company - AdisInsight".
  4. ^ Aghajanian GK, Marek GJ (1999). "Serotonin and Hallucinogens". Neuropharmacology. 21 (2S): 16S–23S. doi:10.1016/s0893-133x(98)00135-3. PMID 10432484.
  5. ^ Halberstadt AL (2017). "Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 32: 283–311. doi:10.1007/7854_2016_64. ISBN 978-3-319-52442-9. PMID 28097528.
  6. ^ Lawn W, Barratt M, Williams M, Horne A, Winstock A (2014). "The NBOMe hallucinogenic drug series: Patterns of use, characteristics of users and self-reported effects in a large international sample". J. Psychopharmacol. (Oxford). 28 (8): 780–8. doi:10.1177/0269881114523866. PMID 24569095. S2CID 35219099.
  7. ^ a b Wood DM, Sedefov R, Cunningham A, Dargan PI (2015). "Prevalence of use and acute toxicity associated with the use of NBOMe drugs". Clin Toxicol. 53 (2): 85–92. doi:10.3109/15563650.2015.1004179. PMID 25658166. S2CID 25752763.
  8. ^ Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE (2013). "Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands". ACS Chem Neurosci. 4 (1): 96–109. doi:10.1021/cn3000668. PMC 3547484. PMID 23336049.
  9. ^ "Indole compounds useful as serotonin selective agents".
  10. ^ a b c Suzuki J, Dekker MA, Valenti ES, Arbelo Cruz FA, Correa AM, Poklis JL, Poklis A (2015). "Toxicities associated with NBOMe ingestion-a novel class of potent hallucinogens: a review of the literature". Psychosomatics. 56 (2): 129–39. doi:10.1016/j.psym.2014.11.002. PMC 4355190. PMID 25659919.
  11. ^ Gillman PK (2006). "A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action". Biol. Psychiatry. 59 (11): 1046–51. doi:10.1016/j.biopsych.2005.11.016. PMID 16460699. S2CID 12179122.
  12. ^ Iqbal MM, Basil MJ, Kaplan J, Iqbal MT (2012). "Overview of serotonin syndrome". Ann Clin Psychiatry. 24 (4): 310–8. PMID 23145389.
  13. ^ a b Hutcheson, J. D., Setola, V., Roth, B. L., & Merryman, W. D. (2011). Serotonin receptors and heart valve disease—it was meant 2B. Pharmacology & Therapeutics, 132(2), 146-157.
  14. ^ Brea, J., Castro-Palomino, J., Yeste, S., Cubero, E., Párraga, A., Domínguez, E., & Loza, M. I. (2010). Emerging Opportunities and Concerns for Drug Discovery at Serotonin 5-HT2B Receptors. Current Topics in Medicinal Chemistry, 10(5), 493-503.
  15. ^ Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364-381.
  16. ^ Zolkowska, D., Rothman, R. B., & Baumann, M. H. (2006). Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. Journal of Pharmacology and Experimental Therapeutics, 318(2), 604-610.
  17. ^ Karila D, Freret T, Bouet V, Boulouard M, Dallemagne P, Rochais C (2015). "Therapeutic Potential of 5-HT6 Receptor Agonists". J. Med. Chem. 58 (20): 7901–12. doi:10.1021/acs.jmedchem.5b00179. PMID 26099069.

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