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.[2]
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.
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.[3][4]
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.[5]
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.[6] The most well-known member of the 25-NB series is 25I-NBOMe.[7][8](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.[9]O-4310 (1-isopropyl-6-fluoropsilocin) is a tryptamine derivative that is a highly selective agonist of the 5-HT2A receptor.[10]
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.[8][11] 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.[11] 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.[11][12] Antagonists of the 5-HT2A receptor like cyproheptadine and chlorpromazine are able to reverse and mediate recovery from serotonin syndrome.[13]
Agonists of the 5-HT2B receptor are implicated in the development of cardiac fibrosis.[14]Fenfluramine, pergolide, and cabergoline have been withdrawn from some markets for this reason.[15] Many serotonergic psychedelics, such as LSD and psilocin, have been shown to activate this receptor directly.[16] MDMA has been reported to be both a potent direct agonist[14] and have an indirect effect by increasing plasma serotonin levels.[17]
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.
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.
^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. PMID28076702. S2CID6034372.
^Iqbal MM, Basil MJ, Kaplan J, Iqbal MT (2012). "Overview of serotonin syndrome". Ann Clin Psychiatry. 24 (4): 310–8. PMID23145389.
^ abHutcheson, 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.
^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.
^Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364-381.
^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.
^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. PMID26099069.
