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Serotonin 5-HT2A receptor agonist

From Wikipedia, the free encyclopedia
Drug class
Serotonin 5-HT2A receptor agonist
Drug class
Psilocybin, a well-known non-selective agonist of the serotonin 5-HT2A receptor and other serotonin receptors and aserotonergic psychedelic.
Class identifiers
Synonyms5-HT2A agonist
UseHallucinogenic effects, treatment ofpsychiatric and otherdisorders
Mechanism of actionSerotonin5-HT2A receptoragonism
Biological targetSerotonin5-HT2A receptor
Chemical classTryptamines,phenethylamines,ergolines,lysergamides, others
Legal status
In Wikidata

Aserotonin 5-HT2A receptor agonist, or simply5-HT2A agonist, is adrug which acts as anagonist of theserotonin5-HT2A receptor.[1][2] The serotonin 5-HT2A receptor is one of 13 known humanserotonin receptors.[3] Serotonin 5-HT2A receptor agonists can be divided into two main groups: (1)serotonergic psychedelics such asLSD,psilocybin, andmescaline; and (2) non-hallucinogenic serotonin 5-HT2A receptor agonists such aslisuride,Ariadne,tabernanthalog, andzalsupindole, among others.[1][4] Psychedelic and non-hallucinogenic serotonin 5-HT2A receptor agonists can be reliably distinguished from each other inscientific research using thehead-twitch responseassay in animals.[5][4][6]

Agonists of the serotonin 5-HT2A receptor are generally notselective for thisreceptor and also interact with other serotonin receptors, such as the serotonin5-HT1A,5-HT2B, and/or5-HT2C receptors, among others.[7][8] However, highly selective serotonin 5-HT2A receptor agonists, such asTGF-8027, have also been developed.[9] In addition to degree of selectivity for the serotonin 5-HT2A receptor, the serotonin 5-HT2A receptor activates a variety of different downstreamsignaling pathways, such asG protein andβ-arrestin cascades, and serotonin 5-HT2A receptor agonists can have varyingefficacies for activating these pathways, in turn resulting in different effects.[10][11][12][8] Differing efficacies at different downstream signaling pathways relative to serotonin is also known asfunctional selectivity orbiased agonism.[10][11]

Serotonin 5-HT2A receptor agonists are frequentlyanalogues of theneurotransmitter serotonin, and includetryptamines,phenethylamines, andergolines andlysergamides, among otherchemical classes.[1][13][14]

In addition to therecreational andentheogenic use of serotonergic psychedelics, both psychedelic and non-hallucinogenic serotonin 5-HT2A receptor agonists, which act aspsychoplastogens and haveantidepressant-like effects in animals, may have applications in the treatment ofpsychiatric disorders such asdepression,anxiety, andaddiction.[15][16] However, use of psychedelics for such purposes has also been critiqued and their potentialadverse effects highlighted.[17][18][19]

Serotonergic psychedelics

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Main articles:Psychedelic drug andSerotonin § Psychedelics

Serotonergic psychedelics, also known as hallucinogenic serotonin 5-HT2A receptor agonists, producehallucinogenic effects includingopen-eye andclosed-eyepsychedelic visuals, otherperceptual changes,synesthesia,time dilation,ego loss,emotional changes, andmystical experiences, among others.[20][21][22][23][24] Examples of serotonergic psychedelics include the following:[1][13]

It is thought that a certain minimum level ofactivationalefficacy at theGq pathway of the serotonin 5-HT2A receptor may be required for psychedelic effects.[10][11][12] However, more research is needed, and a role of other pathways, such as theβ-arrestin pathway, has not been ruled out.[10][14]

Non-hallucinogenic 5-HT2A receptor agonists

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See also:Psychoplastogen andHead-twitch response § Non-hallucinogenic serotonin 5-HT2A receptor agonists

Non-hallucinogenic serotonin 5-HT2A receptor agonists, which have sometimes been referred to as "non-hallucinogenic psychedelics", are a class of drugs which act asagonists of the serotonin 5-HT2A receptor and produce effects mediated by this receptor such asneuroplastic and behavioral changes but do not producepsychedelic effects.[1][4][16][25][26] This class of drugs includes the following compounds:[1][4][16][25][27]

However, most of the above-listed drugs have been concluded to be non-hallucinogenic based on animal behavioral measures of psychedelic-like effects such as thehead-twitch response (HTR)assay in rodents. Many of these drugs have not been tested in humans and their putatively non-hallucinogenic natures have not been confirmed. Although available evidence is limited, some observations suggest that hallucinogenic effects may emerge at higher doses in some cases. For instance, whiletabernanthalog has been reported to be non-hallucinogenic based onpreclinical research,anecdotal reports suggest that it can produce mild hallucinogenic effects at sufficiently high doses in humans.[28][29][30] Additionally,hallucinations have been observed in humans with high doses oflisuride, which is an often-cited non-hallucinogenic serotonin 5-HT2A receptor agonist related to LSD, although the nature and mechanisms of these apparent hallucinogenic effects are unclear anddopamineD2 receptor agonism might alternatively be involved.[31] Another drug,JRT, is theisoindoleanalogue of LSD and has reduced or possibly absent psychedelic-like effects in animals.[32][33]

The precisemechanism by which non-hallucinogenic serotonin 5-HT2A receptor agonists lack psychedelic effects is uncertain; it is thought that they may not activate the serotonin 5-HT2A receptor with sufficientefficacy, possibly specifically with regard to theGq pathway, to produce hallucinogenic effects.[11] However, many of these drugs have nonetheless been found to producepsychoplastogenic effects mediated by serotonin 5-HT2A receptor activation and to an equivalent extent as with psychedelics.[34][35][36][37] This might be involved in theantidepressant-like effects of these drugs per animal studies, and non-hallucinogenic serotonin 5-HT2A receptor agonists may have therapeutic potential similarly to psychedelics.[37][38][39][40][41]

Inpreclinical models, animals administered non-hallucinogenic serotonin 5-HT2A receptor agonists exhibit fewer hallucinogen-associated behaviors at doses that produce rapid antidepressant-like effects.[42][28] The psychoplastogenic effects of non-hallucinogenic serotonin 5-HT2A receptor agonists appear to coincide with their rapid antidepressant-like effects inanimal models.[41] It has been suggested that non-hallucinogenic serotonin 5-HT2A receptor agonists may be more suitable for broader clinical use compared to psychedelics because of their reduced perception-altering effects.[43]

Selective 5-HT2A receptor agonists

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Selective serotonin 5-HT2A receptor agonists are known and include25CN-NBOH,BMB-202,DMBMPP,DOI-NBOMe,LPH-5,LPH-48, andTGF-8027.[1][44][45][9][27]

Biased 5-HT2A receptor agonists

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The serotonin 5-HT2A receptor is coupled to multiple downstreamsignaling pathways.[11][46][10][14] A number ofbiased agonists of the serotonin 5-HT2A receptor are known.[46][11] These include theG protein-biasedlisuride,[47](R)-69,[48] and(R)-70;[48] theβ-arrestin-biasedLSD,[47]RS130-180,[49]25CN-NBOH andderivatives,[46][50]25N-N1-Nap,[12]25N-NBPh,[12]IHCH-7079,[42] andIHCH-7086;[42] and others likeDOI-NBOMe,[27]TCB-2 (2CBCB),[51][52] and5-phenoxytryptamine (OVT2).[46][53] Thefunctional selectivity of variousserotonergic psychedelics at the serotonin 5-HT2A receptor has been studied.[54][55][56][57] Besides the serotonin 5-HT2A receptor, many psychedelics are biased agonists of the serotonin5-HT2C receptor.[58]

Peripherally selective 5-HT2A receptor agonists

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See also:Serotonin 5-HT2A receptor § Peripherally selective agonists, andPeripherally selective drug § List of peripherally selective drugs

Peripherally selective serotonin 5-HT2A receptor agonists that lack effects on thebrain are known.[1][59][31] Aside fromserotonin itself,[24]α-methylserotonin,[24][60] and the partially peripherally selectivebufotenin (N,N-dimethylserotonin),[59][14][61] another notable example of a peripherally selective serotonin 5-HT2A receptor agonist isAL-34662.[62][63] This drug was investigated for the potential treatment ofeye diseases such asocular hypertension andglaucoma.[62][63]Ergotamine may also be a peripherally selective serotonin 5-HT2A receptor agonist, and is used as anobstetric drug andantimigraine agent.[31][64]Psilocybin andpsilocinanalogues found inpsilocybin-containing mushrooms, includingbaeocystin,norpsilocin,aeruginascin, and4-HO-TMT, have been found to be peripherally selective serotonin 5-HT2A receptor agonists as well.[65][66][67][68]

Selected effects of 5-HT2A receptor agonists

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Anti-inflammatory 5-HT2A receptor agonists

[edit]
Main article:Serotonin 5-HT2A receptor § Anti-inflammatory effects

Some serotonergic psychedelics, such as(R)-DOI andpsilocybin, show highlypotentanti-inflammatory effects mediated by serotonin 5-HT2A receptor activation.[69][70][71][72][73] Other serotonergic psychedelics, such asLSD, are less potent, and yet other psychedelics, likeDOTFM, show no anti-inflammatory effects at all.[70][73][74] Conversely, some serotonin 5-HT2A receptor agonists, such as2,5-DMA, have potent anti-inflammatory effects with no apparent psychedelic effects.[73][75][74] These findings indicate that the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists are mediated by different downstream signaling pathways and are fully dissociable.[73][75][74] Serotonin 5-HT2A receptor agonists with reduced psychedelic potential but retained anti-inflammatory effects, such as2C-iBu (ELE-02), are being studied to treatinflammatory disorders.[76][77][78]

5-HT2A receptor agonists and organ fibrosis

[edit]
See also:Psychedelic microdosing § Long-term toxicity

Many serotonin 5-HT2A receptor agonists, due to lack ofselectivity and activation of the closely related serotonin5-HT2B receptor,[79][8][12] may have the potential to produceorganfibrosis and associated complications such ascardiac valvulopathy orpulmonary hypertension with long-term use.[80][81][82][83] This has been observed withpharmaceutical drugs such asfenfluramine,methysergide,ergotamine,cabergoline, andpergolide, among others, which has led tomarket withdrawal or restrictions on use of such agents.[84][85][86][87][88] Infrequent or occasional use of serotonergic psychedelics is thought to be safe and not pose a significant risk, but very frequent use ormicrodosing may carry risk.[80][82][89] Not all serotonin 5-HT2A receptor agonists are alsopotent serotonin 5-HT2B receptor agonists however.[79][8][12] For example, manyphenethylamine psychedelics show substantialselectivity for the serotonin 5-HT2A and5-HT2C receptors over the serotonin 5-HT2B receptor.[79][8][12] In addition, selective serotonin 5-HT2A receptor agonists that show less or no activation of otherserotonin receptors such as the serotonin 5-HT2B receptor, such as25CN-NBOH,DMBMPP,LPH-5, andTGF-8027, have been developed.[1][90][9] Moreover, selective serotonin 5-HT2B receptorantagonists, includingperipherally selective drugs likeVU0530244, are being developed, and may be able to block the complications of serotonin 5-HT2B receptor agonism.[86][91][92][93][94]

5-HT2A receptor agonists and neurotoxicity

[edit]
See also:Psychedelic drug § Neurotoxicity

Serotonin 5-HT2A receptor agonists may produceneurotoxicity, for instanceserotonergic neurotoxicity, at high concentrations or doses.[95][96][97][98] In addition, they may potentiate the serotonergic neurotoxicity ofMDMA.[99][100][101][102]

Indirect 5-HT2A receptor agonists

[edit]
See also:5-HT2A receptor § Serotonin-elevating drugs,Serotonin § Psychedelics, andPsychedelic drug § Mechanism of action

Serotonergic agents that elevate serotonin levels can act as indirect serotonin 5-HT2A receptor agonists.[103][104] Examples of such agents includeserotonin precursors liketryptophan and5-hydroxytryptophan (5-HTP),serotonin reuptake inhibitors (SRIs) likeselective serotonin reuptake inhibitors (SSRIs) and various otherantidepressants,monoamine oxidase inhibitors (MAOIs), andserotonin releasing agents (SRAs) likefenfluramine andMDMA.[103][104][105][106][107][108][109][110] Direct serotonin 5-HT2A receptor agonists and serotonin-elevating drugs have differing effects.[36] As an example, whereas serotonin-elevating drugs have a risk ofserotonin syndrome, major serotonergic psychedelics likepsilocybin andLSD arepartial agonists of the serotonin 5-HT2A receptor and have little or no risk of serotonin syndrome even in the context of largeoverdoses.[111][112][113] However, one notable group of psychedelics, theNBOMe drugs, have higherefficacy at the serotonin 5-HT2A receptor and can produce serotonin syndrome.[112] As another example, serotonin is a highlyhydrophilicmolecule and is unable to enterneurons and activateintracellular serotonin 5-HT2A receptors, which have been found to mediate the psychoplastogenic effects ofexogenous serotonin 5-HT2A receptor agonists.[114][36][115] These intracellular serotonin 5-HT2A receptors may also contribute to the psychedelic effects of serotonin 5-HT2A receptor agonists.[36]

See also

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References

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Tryptamines
No ring subs.
4-Hydroxytryptamines
5-Hydroxytryptamines
5-Methoxytryptamines
Other ring subs.
α-Alkyltryptamines
Others
Cyclized
Bioisosteres
Phenethylamines
Scalines
2C-x
3C-x
DOx
4C-x
Ψ-PEA
MDxx
FLY
25x-NB (NBOMes)
Others
Cyclized
Lysergamides
Others
Natural sources
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
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