Serotonin receptor agonist

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The neurotransmitter serotonin (illustration) has various receptors. Serotonin-2D-skeletal.svg
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.

Contents

Non-selective agonists

Serotonergic psychedelics such as tryptamines (e.g., psilocybin, psilocin, DMT, 5-MeO-DMT, bufotenin), lysergamides (e.g., LSD, ergine (LSA)), phenethylamines (e.g., mescaline, 2C-B, 25I-NBOMe), and amphetamines (e.g., MDA, DOM) 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, MDMA), 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

5-HT1A receptor agonists

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

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

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

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

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

5-HT2A receptor agonists

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

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

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

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

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

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

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

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

See also

Related Research Articles

<span class="mw-page-title-main">Triptan</span> Class of pharmaceutical drugs

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.

<span class="mw-page-title-main">Methysergide</span> Chemical compound

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.

<span class="mw-page-title-main">Antimigraine drug</span> Medication intended to reduce the effects or intensity of migraine headache

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

<span class="mw-page-title-main">TCB-2</span> Potent hallucinogenic drug discovered in 2006

TCB-2 is a hallucinogen discovered in 2006 by Thomas McLean working in the lab of David Nichols at Purdue University. It is a conformationally-restricted derivative of the phenethylamine 2C-B, also a hallucinogen, and acts as a potent agonist for the 5-HT2A and 5-HT2C receptors with a Ki of 0.26 nM at the human 5-HT2A receptor. In drug-substitution experiments in rats, TCB-2 was found to be of similar potency to both LSD and Bromo-DragonFLY, ranking it among the most potent phenethylamine hallucinogens yet discovered. This high potency and selectivity has made TCB-2 useful for distinguishing 5-HT2A mediated responses from those produced by other similar receptors. TCB-2 has similar but not identical effects in animals to related phenethylamine hallucinogens such as DOI, and has been used for studying how the function of the 5-HT2A receptor differs from that of other serotonin receptors in a number of animal models, such as studies of cocaine addiction and neuropathic pain.

<span class="mw-page-title-main">25I-NBOMe</span> Synthetic hallucinogen

25I-NBOMe is a synthetic hallucinogen that is used in biochemistry research for mapping the brain's usage of the type 2A serotonin receptor; it is also sometimes used for recreational purposes. A derivative of the substituted phenethylamine 2C-I family, it is the most well-known member of the 25-NB family. It was discovered in 2003 by chemist Ralf Heim at the Free University of Berlin, who published his findings in his PhD dissertation. The compound was subsequently investigated by a team at Purdue University led by David Nichols.

<span class="mw-page-title-main">Quipazine</span> Chemical compound

Quipazine is a serotonergic drug of the piperazine group which is used in scientific research. It was originally intended as an antidepressant but never developed for medical use.

Triptans is a word commonly used for a class of anti-migraine drugs that are selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists. Migraine is a complex disease which affects about 15% of the population and can be highly disabling. Triptans have advantages over ergotamine and dihydroergotamine, such as selective pharmacology, well established safety record and evidence-based prescribing instructions. Triptans are therefore often preferred treatment in migraine.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

<span class="mw-page-title-main">25B-NBOMe</span> Chemical compound

25B-NBOMe is a derivative of the phenethylamine psychedelic 2C-B, discovered in 2004 by Ralf Heim at the Free University of Berlin. It acts as a potent full agonist for the 5HT2A receptor. Anecdotal reports from users suggest 25B-NBOMe to be an active hallucinogen at a dose of as little as 250–500 µg, making it a similar potency to other phenethylamine derived hallucinogens such as Bromo-DragonFLY. Duration of effects lasts about 12–16 hours, although the parent compound is rapidly cleared from the blood when used in the radiolabeled form in tracer doses. Recently, Custodio et al (2019) evaluated the potential involvement of dysregulated dopaminergic system, neuroadaptation, and brain wave changes which may contribute to the rewarding and reinforcing properties of 25B-NBOMe in rodents.

<span class="mw-page-title-main">25TFM-NBOMe</span> Chemical compound

25TFM-NBOMe is a derivative of the phenethylamine hallucinogen 2C-TFM, discovered in 2004 by Ralf Heim at the Free University of Berlin. It acts as a potent partial agonist for the 5HT2A receptor, though its relative potency is disputed, with some studies finding it to be of lower potency than 25I-NBOMe, while others show it to be of similar or higher potency, possibly because of differences in the assay used. 2C-TFM-NB2OMe can be taken to produce psychedelic effects similar to 2C-I-NB2OMe and 2C-D-NB2OMe.

<span class="mw-page-title-main">25C-NBOMe</span> Psychedelic drug

25C-NBOMe is a psychedelic drug and derivative of the psychedelic phenethylamine 2C-C. 25C-NBOMe appeared on online vendor sites in 2010 but was not reported in the literature until 2011. It acts as a potent agonist of the 5HT2A receptor, and has been studied in its 11C radiolabelled form as a potential ligand for mapping the distribution of 5-HT2A receptors in the brain, using positron emission tomography (PET). Multiple deaths have occurred from usage of 25C-NBOMe due to the ease of accidental overdose. The long-term toxic effects of the drug have not been researched.

<span class="mw-page-title-main">25D-NBOMe</span> Chemical compound

25D-NBOMe is a derivative of the phenethylamine derived hallucinogen 2C-D. It acts in a similar manner to related compounds such as 25I-NBOMe, which is a potent agonist at the 5HT2A receptor. 25D-NBOMe has been sold as a street drug since 2010 and produces similar effects in humans to related compounds such as 25I-NBOMe and 25C-NBOMe. It was banned as a Temporary Class Drug in the UK on 10 June 2013 after concerns about its recreational use.

<span class="mw-page-title-main">25N-NBOMe</span> Chemical compound

25N-NBOMe is a derivative of the hallucinogen 2C-N. The pharmacological properties of 25N-NBOMe have not been described in the scientific literature, but it is believed to act in a similar manner to related compounds such as 25I-NBOMe and 25C-NBOMe, which are potent agonists at the 5HT2A receptor. 25N-NBOMe has been sold as a street drug and has only been described in the literature in terms of identification by forensic analysis.

<span class="mw-page-title-main">25E-NBOMe</span> Chemical compound

25E-NBOMe is a derivative of the phenethylamine 2C-E. It acts in a similar manner to related compounds such as 25I-NBOMe, which are potent agonists at the 5HT2A receptor. 25E-NBOMe has been sold as a drug and produces similar effects in humans to related compounds such as 25I-NBOMe and 25C-NBOMe.

A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, is a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

<span class="mw-page-title-main">25G-NBOMe</span> Chemical compound

25G-NBOMe (NBOMe-2C-G) is a derivative of the phenethylamine hallucinogen 2C-G, which acts as a highly potent agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25H-NBOMe</span> Chemical compound

25H-NBOMe (NBOMe-2C-H) is a derivative of the phenethylamine hallucinogen 2C-H, which acts as a highly potent full agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25iP-NBOMe</span> Chemical compound

25iP-NBOMe is a derivative of the phenethylamine hallucinogen 2C-iP, which acts as a highly potent agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25-NB</span> Family of serotonergic psychedelics

The 25-NB (25x-NBx) series, sometimes alternatively referred to as the NBOMe compounds, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C family. They act as selective agonists of the serotonin 5-HT2A receptor. The 25-NB family is unique relative to other classes of psychedelics in that they are, generally speaking, extremely potent and relatively selective for the 5-HT2A receptor. Use of NBOMe series drugs has caused many deaths and hospitalisations since the drugs popularisation in the 2010s. This is primarily due to their high potency, unpredictable pharmacokinetics, and sellers passing off the compounds in the series as LSD.

References

  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. 1 2 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. 1 2 3 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. 1 2 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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