5-HT2A receptor

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5-hydroxytryptamine (serotonin) receptor 2A, G protein-coupled
Identifiers
SymbolsHTR2A; 5-HT2A; HTR2
External IDsOMIM: 182135 MGI: 109521 HomoloGene: 68073 IUPHAR: 5-HT2A ChEMBL: 224 GeneCards: HTR2A Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez335615558
EnsemblENSG00000102468ENSMUSG00000034997
UniProtP28223P35363
RefSeq (mRNA)NM_000621NM_172812
RefSeq (protein)NP_000612NP_766400
Location (UCSC)Chr 13:
47.41 – 47.47 Mb		Chr 14:
74.64 – 74.71 Mb
PubMed search
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The mammalian 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).[1] This is the main excitatory receptor subtype among the GPCRs for serotonin (5-HT), although 5-HT2A may also have an inhibitory effect[2] on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first given importance as the target of serotonergic psychedelic drugs such as LSD. 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.

5-HT2A may be a necessary receptor for the spread of the human polyoma virus called JC virus.[3]

Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of SSRIs and classical antipsychotics. Deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression.[4]

History

Serotonin receptors were split into two classes by Gaddum and Picarelli when it was discovered that some of the serotonin-induced changes in the gut could be blocked by morphine, whilst the remainder of the response was inhibited by dibenzyline leading to the naming of M and D receptors respectively. 5-HT2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli.[5] In the pre-molecular-cloning era when radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different serotonin receptors, and neither of them displaced morphine, leading to naming of the 5-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine respectively.[6] Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, renaming the 5-HT2 into 5-HT2A. Thus the 5-HT2 receptor family is composed of three separate molecular entities: the 5-HT2A (formerly known as 5-HT2 or D), the 5-HT2B (formerly known as 5-HT2F) and the 5-HT2C (formerly known as 5-HT1C) receptors.[7]

Distribution

5-HT2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes,[8][9][10] by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A,[11] GABAA,[12] adenosine A1,[13] AMPA,[14] mGluR2/3,[15] mGlu5,[16] and OX2 receptors.[17][18] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,[19] and in the Purkinje cells.[20][21]

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in human monocytes.[22]

Signaling cascade

The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca2+ release.[23]

There are many additional signal cascade components that include the formation of arachidonic acid through PLA2 activity, activation of phospholipase D, Rho/Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor.[citation needed]

Effects

Physiological processes mediated by the receptor include:

Ligands

Agonists

Activation of the 5-HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched.[28][29] Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by monomeric 5-HT2A receptors.[30][31][32]

Full agonists

Partial agonists

  • Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial agonist, in some preparations.
  • The atypical antipsychotic aripiprazole is also a weak partial agonist.[37]
  • OSU-6162 acts as a partial agonist at both 5-HT2A and dopamine D2 receptors
  • NBOH-2C-CN, 100x selectivity for 5-HT2A over 5-HT2C, 46x selectivity over 5-HT2B.[38]
  • (2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine is a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124x selectivity for 5-HT2A over 5-HT2C, making it the most selective agonist ligand identified to date.[39]
  • Cannabidiol, a phytocannbinoid in Cannabis.[40]
  • Efavirenz, an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A.[41]

Peripherally selective agonists

One effect of 5-HT2A receptor activation is a reduction in intraocular pressure, and so 5-HT2A agonists can be useful for the treatment of glaucoma. This has led to the development of compounds such as AL-34662 that are hoped to reduce pressure inside the eyes but without crossing the blood–brain barrier and producing hallucinogenic side effects.[42] Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the head twitch response known to be characteristic of hallucinogenic effects in rodents.[43]

Silent antagonists

  • Although ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as metergoline bind preferentially to members of the 5-HT2 receptor family.
  • The discovery of Ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibits 5-HT2C receptors.
  • Nefazodone operates by blocking post-synaptic serotonin type-2A receptors and to a lesser extent by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake.
  • Atypical antipsychotic drugs like clozapine, olanzapine, quetiapine, risperidone and asenapine are relatively potent antagonists of 5-HT2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are MDL-100,907 (prototype of another new series of 5-HT2Aantagonists) and cyproheptadine.
  • Pizotifen is a non-selective antagonist.[44]
  • LY-367,265 - dual 5-HT2A antagonist / SSRI with antidepressant effects
  • 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).[45]
  • AMDA and related derivatives are another family of selective 5-HT2A antagonists.[46][47][48][49][50]
  • Hydroxyzine (Atarax)
  • 5-MeO-NBpBrT

Inverse agonists

Functional selectivity

5-HT2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.[58]

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce headshakes in the mouse and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists.[59][60] One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2.[61][62]

Role of lipophilicity

A set of ligands were evaluated. For agonists, a highly significant linear correlation was observed between binding affinity and lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity.[63]

Genetics

Chromosome 13.

The 5-HT2A receptors is coded by the HTR2A gene. In humans the gene is located on chromosome 13. The gene has previously been called just HTR2 until the description of two related genes HTR2B and HTR2C. Several interesting polymorphisms have been identified for HTR2A: A-1438G (rs6311), C102T (rs6313) and His452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.[64]

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as bipolar disorder[65] and major depressive disorder.[66] A weak link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.[67] This polymorphism has also been studied in relation to suicide attempts, with a study finding excess of the C/C genotypes among the suicide attempters.[68] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[69]

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies [of HTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.[70]

Treatment response

One study has found that genetic variations between individuals in the HTR2A gene may to some extent account for the difference in outcome of antidepressant treatment, so that patients suffering from major depressive disorder and treated with Citalopram may benefit more than others if they have one particular genotype.[71] In this study 768 single nucleotide polymorphism (SNP) across 68 genes were investigated and a SNP—termed rs7997012—in the second intron of the HTR2A gene showed significant association with treatment outcome.

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.[72][73]

One study has also linked abnormal 5-HT2A polymorphisms which may enhance receptor activity with Chronic Fatigue Syndrome.[74]

Neuroimaging

The 5-HT2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin[75] and MDL 100,907[76] radioligands that binds to the neuroreceptor, e.g., one study reported a reduced binding of altanserin particularly in the hippocampus in patients with major depressive disorder.[77] Another PET study reported increased altanserin binding in the caudate nuclei in obsessive compulsive disorder patients compared to a healthy control group.[78]

Patients with Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls.[79] The altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age.[80][81][82] A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait neuroticism as measured by the NEO PI-R personality questionnaire.[83]

Role in virus endocytosis

5-HT2A may be a necessary receptor for clathrin mediated endocytosis of the human polyoma virus called JC virus, the causative agent of progressive multifocal leukoencephalopathy (PML), that enters cells such as oligodendrocytes, astrocytes, B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked sialic acid component of the 5-HT2A receptor in order to endocytose JCV.[3]

References

  1. ↑ Cook EH, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL (August 1994). "Primary structure of the human platelet serotonin 5-HT2 receptor: identity with frontal cortex serotonin 5-HT2A receptor". J. Neurochem. 63 (2): 465–469. doi:10.1046/j.1471-4159.1994.63020465.x. PMID 8035173. 
  2. ↑ Martin P, Waters N, Schmidt CJ, Carlsson A, Carlsson ML. (1998). "Rodent data and general hypothesis: antipsychotic action exerted through 5-Ht2A receptor antagonism is dependent on increased serotonergic tone". J Neural Transm 105 (4–5): 365–396. PMID 9720968. 
  3. ↑ 3.0 3.1 Elphick GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, Dugan A, Stanifer M, Bhatnagar A, Kroeze WK, Roth BL, Atwood WJ (2004). "The human polyomavirus, JCV, uses serotonin receptors to infect cells". Science 306 (5700): 1380–3. doi:10.1126/science.1103492. PMID 15550673. 
  4. ↑ Eison AS, Mullins UL (1996). "Regulation of central 5-HT2A receptors: a review of in vivo studies". Behavioural Brain Research 73 (1–2): 177–81. doi:10.1016/0166-4328(96)00092-7. PMID 8788498. 
  5. ↑ Sanders-Bush E, Mayer SE (2006). "Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists". In Brunton LL, Lazo JS, Parker K. Goodman & Gilman's the Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 0-07-142280-3. 
  6. ↑ George J. Siegel, R. Wayne Albers (2005). Basic neurochemistry: molecular, cellular, and medical aspects 1 (7th ed ed.). Academic Press. p. 241. ISBN 0-12-088397-X. 
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  8. ↑ Aghajanian GK, Marek GJ (April 1999). "Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release". Brain Res. 825 (1-2): 161–71. doi:10.1016/S0006-8993(99)01224-X. PMID 10216183. 
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  11. ↑ Amargós-Bosch M, Bortolozzi A, Puig MV, Serrats J, Adell A, Celada P, Toth M, Mengod G, Artigas F (March 2004). "Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex". Cereb. Cortex 14 (3): 281–99. doi:10.1093/cercor/bhg128. PMID 14754868. 
  12. ↑ Feng J, Cai X, Zhao J, Yan Z (September 2001). "Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons". J. Neurosci. 21 (17): 6502–6511. PMID 11517239. 
  13. ↑ Marek GJ (March 2009). "Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats". Neuropharmacology 56 (8): 1082–7. doi:10.1016/j.neuropharm.2009.03.005. PMC 2706691. PMID 19324062. 
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  16. ↑ Marek GJ, Zhang C (September 2008). "Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex". Neurosci. Lett. 442 (3): 239–43. doi:10.1016/j.neulet.2008.06.083. PMC 2677702. PMID 18621097. 
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  19. ↑ Geurts FJ, De Schutter E, Timmermans JP (June 2002). "Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum". Journal of chemical neuroanatomy 24 (1): 65–74. doi:10.1016/S0891-0618(02)00020-0. PMID 12084412. 
  20. ↑ Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N (August 1998). "Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells". Neurosci. Lett. 252 (1): 72–74. doi:10.1016/S0304-3940(98)00546-1. PMID 9756362. 
  21. ↑ Maeshima T, Shiga T, Ito R, Okado N (December 2004). "Expression of serotonin2A receptors in Purkinje cells of the developing rat cerebellum". Neurosci. Res. 50 (4): 411–417. doi:10.1016/j.neures.2004.08.010. PMID 15567478. 
  22. ↑ Dürk T, Panther E, Müller T, Sorichter S, Ferrari D, Pizzirani C, Di Virgilio F, Myrtek D, Norgauer J, Idzko M. (May 2005). "5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes". Int Immunol 17 (5): 599–606. doi:10.1093/intimm/dxh242. PMID 15802305. 
  23. ↑ Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007). "Functional selectivity and classical concepts of quantitative pharmacology". J. Pharmacol. Exp. Ther. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID 16803859. 
  24. ↑ Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (November 2008). "Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-_-induced inflammation with extraordinary potency". J. Pharmacol. Exp. Ther. 327 (2): 316–323. doi:10.1124/jpet.108.143461. PMID 18708586. 
  25. ↑ Nau F, Yu B, Martin D, Nichols CD (2013). "Serotonin 5-HT2A Receptor Activation Blocks TNF-a Mediated Inflammation In Vivo". PLOS One 8 (10): e75426. doi:10.1371/journal.pone.0075426. PMID 24098382. 
  26. ↑ Van De Kar, L. D.; Javed, A.; Zhang, Y.; Serres, F.; Raap, D. K.; Gray, T. S. (2001). "5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells". The Journal of neuroscience : the official journal of the Society for Neuroscience 21 (10): 3572–3579. PMID 11331386. 
  27. ↑ Zhang Y, Damjanoska KJ, Carrasco GA, Dudas B, D'Souza DN, Tetzlaff J, Garcia F, Hanley NR, Scripathirathan K, Petersen BR, Gray TS, Battaglia G, Muma NA, Van de Kar LD (November 2002). "Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI". J Neurosci. 22 (21): 9635–9642. PMID 12417689. 
  28. ↑ Nichols, DE (2004). "Hallucinogens.". Pharmacology & therapeutics 101 (2): 131–181. doi:10.1016/j.pharmthera.2003.11.002. PMID 14761703. 
  29. ↑ Blaazer AR, Smid P, Kruse CG. Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT2A receptors. ChemMedChem. 2008 Sep;3(9):1299-309. PMID 18666267
  30. ↑ Moreno, J. L.; Muguruza, C.; Umali, A.; Mortillo, S.; Holloway, T.; Pilar-Cuéllar, F.; Mocci, G.; Seto, J.; Callado, L. F.; Neve, R. L.; Milligan, G.; Sealfon, S. C.; López-Giménez, J. F.; Meana, J. J.; Benson, D. L.; González-Maeso, J. (2012). "Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A{middle dot}mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function". Journal of Biological Chemistry 287 (53): 44301–44319. doi:10.1074/jbc.M112.413161. PMC 3531745. PMID 23129762. 
  31. ↑ González-Maeso, J.; Ang, R. L.; Yuen, T.; Chan, P.; Weisstaub, N. V.; López-Giménez, J. F.; Zhou, M.; Okawa, Y.; Callado, L. F.; Milligan, G.; Gingrich, J. A.; Filizola, M.; Meana, J. J.; Sealfon, S. C. (2008). "Identification of a serotonin/glutamate receptor complex implicated in psychosis". Nature 452 (7183): 93–97. doi:10.1038/nature06612. PMC 2743172. PMID 18297054. 
  32. ↑ Moreno, J. L.; Holloway, T.; Albizu, L.; Sealfon, S. C.; González-Maeso, J. (2011). "Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists". Neuroscience Letters 493 (3): 76–79. doi:10.1016/j.neulet.2011.01.046. PMC 3064746. PMID 21276828. 
  33. ↑ Braden MR, Parrish JC, Naylor JC, Nichols DE (2006). "Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists". Mol. Pharmacol. 70 (6): 1956–1964. doi:10.1124/mol.106.028720. PMID 17000863. 
  34. ↑ McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE (September 2006). "1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists". Journal of Medical Chemistry 49 (19): 5794–803. doi:10.1021/jm060656o. PMID 16970404. 
  35. ↑ Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE (March 2001). "Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists". Journal of Medicinal Chemistry 44 (6): 1003–10. doi:10.1021/jm000491y. PMID 11300881. 
  36. ↑ Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Olson, R. M.; Knauer, C. S.; Chio, C. L.; Hyslop, D. K.; Campbell, J. E.; Fitzgerald, L. W.; Nichols, N. F.; Svensson, K. A.; McCall, R. B.; Haber, C. L.; Kagey, M. L.; Dinh, D. M. (2003). "2,3,4,5-Tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-\1,4]diazepino\1,7-a]indoles: New templates for 5-HT2C agonists". Bioorganic & Medicinal Chemistry Letters 13 (14): 2369. doi:10.1016/S0960-894X(03)00403-7. 
  37. ↑ Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu L, Sibley DR, Roth BL, Mailman R (May 2003). "Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology". Neuropsychopharmacology 28 (8): 1400–1411. doi:10.1038/sj.npp.1300203. PMID 12784105. 
  38. ↑ Martin Hansen PhD. Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain. University of Copenhagen, 2011.
  39. ↑ Juncosa, J. I.; Hansen, M.; Bonner, L. A.; Cueva, J. P.; Maglathlin, R.; McCorvy, J. D.; Marona-Lewicka, D.; Lill, M. A.; Nichols, D. E. (2012). "Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands". ACS Chemical Neuroscience 4: 120717095020003. doi:10.1021/cn3000668. 
  40. ↑ Russo, E. B.; Burnett, A.; Hall, B.; Parker, K. K. (2005). "Agonistic Properties of Cannabidiol at 5-HT1a Receptors". Neurochemical Research 30 (8): 1037–1043. doi:10.1007/s11064-005-6978-1. PMID 16258853. 
  41. ↑ Gatch, M. B.; Kozlenkov, A.; Huang, R. Q.; Yang, W.; Nguyen, J. D.; González-Maeso, J.; Rice, K. C.; France, C. P.; Dillon, G. H.; Forster, M. J.; Schetz, J. A. (2013). "The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties". Neuropsychopharmacology. doi:10.1038/npp.2013.135. PMID 23702798. 
  42. ↑ Sharif NA, McLaughlin MA, Kelly CR (February 2007). "AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist". Journal of Ocular Pharmacology and Therapeutics 23 (1): 1–13. doi:10.1089/jop.2006.0093. PMID 17341144. 
  43. ↑ May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA (January 2006). "1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity". Journal of Medicinal Chemistry 49 (1): 318–328. doi:10.1021/jm050663x. PMID 16392816. 
  44. ↑ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 187
  45. ↑ Shireman BT, Dvorak CA, Rudolph DA, Bonaventure P, Nepomuceno D, Dvorak L, Miller KL, Lovenberg TW, Carruthers NI (March 2008). "2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists". Bioorganic & Medicinal Chemistry Letters 18 (6): 2103–8. doi:10.1016/j.bmcl.2008.01.090. PMID 18282705. 
  46. ↑ Westkaemper RB, Runyon SP, Bondarev ML, Savage JE, Roth BL, Glennon RA (September 1999). "9-(Aminomethyl)-9,10-dihydroanthracene is a novel and unlikely 5-HT2A receptor antagonist". Eur. J. Pharmacol. 380 (1): R5–7. doi:10.1016/S0014-2999(99)00525-7. PMID 10513561. 
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  48. ↑ Peddi S, Roth BL, Glennon RA, Westkaemper RB (December 2003). "Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT2A receptor antagonist". Eur. J. Pharmacol. 482 (1-3): 335–7. doi:10.1016/j.ejphar.2003.09.059. PMID 14660041. 
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