4-Desmethylene-LSD

{{cs1 config|name-list-style=vanc|display-authors=6}} {{About|4-nor-LSD|other nor-LSD compounds|Nor-LSD (disambiguation)}} {{Infobox drug | drug_name = 4-Desmethylene-LSD | image = DEIMDHPCA structure.svg | image_class = skin-invert-image | width = 165px | caption =

| legal_status =

| IUPAC_name = (3''R'')-''N'',''N''-diethyl-5-(1''H''-indol-4-yl)-1-methyl-3,6-dihydro-2''H''-pyridine-3-carboxamide | C=19 | H=25 | N=3 | O=1 | SMILES = CCN(CC)C(=O)[C@H]1CN(CC(=C1)C2=C3C=CNC3=CC=C2)C | StdInChI = 1S/C19H25N3O/c1-4-22(5-2)19(23)15-11-14(12-21(3)13-15)16-7-6-8-18-17(16)9-10-20-18/h6-11,15,20H,4-5,12-13H2,1-3H3/t15-/m1/s1 | StdInChIKey = GDCMLRPQENDWLG-OAHLLOKOSA-N }}

'''4-Desmethylene-LSD''', also known as '''4-nor-LSD''', '''3,5-seco-LSD''', or '''DEIMDHPCA''', is an indole derivative and a "partial" or simplified lysergamide which is closely related to the highly potent serotonergic psychedelic lysergic acid diethylamide (LSD).<ref name="WO2021076572">{{cite patent | country = WO | number = 2021076572 | inventor = Olson DE, Dunlap L, Wagner F, Chytil M, Powell NA | status = | title = Ergoline-like compounds for promoting neural plasticity | pubdate = 22 April 2021 | gdate = | fdate = 14 October 2020 | pridate = 14 October 2020 | assign1 = Delix Therapeutics, Inc. | assign2 = The Regents of the University of California | url =https://patents.google.com/patent/WO2021076572/ }}</ref><ref name="PubChem">{{cite web | title=(3R)-N,N-diethyl-5-(1H-indol-4-yl)-1-methyl-3,6-dihydro-2H-pyridine-3-carboxamide | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/156278040 | access-date=21 March 2025}}</ref> It is specifically the analogue of LSD in which one of LSD's carbon atoms in the ergoline ring system, the carbon at position 4, has been removed.<ref name="WO2021076572" /><ref name="PubChem" /> This in turn renders the molecule more flexible and makes it a partially conformationally constrained indolic phenethylamine-containing compound rather than an ergoline.<ref name="WO2021076572" /><ref name="PubChem" /> 4-Desmethylene-LSD is known to be a highly potent serotonin 5-HT2 receptor agonist similarly to LSD and to produce psychoplastogenic effects.<ref name="WO2021076572" />

==Pharmacology== ===Pharmacodynamics=== Like LSD, the drug is known to be a highly potent serotonin 5-HT2A and 5-HT2C receptor agonist ''in vitro''.<ref name="WO2021076572" /> Its affinities ({{Abbrlink|IC50|half-maximal inhibitory concentration}}) are in the ranges of 10–100{{nbsp}}nM for the serotonin 5-HT2A receptor and 100–1,000{{nbsp}}nM for the serotonin 5-HT2C receptor, while its activational potencies ({{Abbrlink|EC50|half-maximal effective concentration}}) are less than 10{{nbsp}}nM for the serotonin 5-HT2A receptor and in the range of 10–100{{nbsp}}nM for the serotonin 5-HT2C receptor.<ref name="WO2021076572" /> 4-Desmethylene-LSD was the most potent serotonin 5-HT2A receptor agonist of 27{{nbsp}}evaluated ergoline-like compounds.<ref name="WO2021076572" /> In line with its serotonin 5-HT2A receptor agonism, and similarly to LSD and other psychedelics,<ref name="HatzipantelisOlson2024">{{cite journal | vauthors = Hatzipantelis CJ, Olson DE | title = The Effects of Psychedelics on Neuronal Physiology | journal = Annu Rev Physiol | volume = 86 | issue = | pages = 27–47 | date = February 2024 | pmid = 37931171 | pmc = 10922499 | doi = 10.1146/annurev-physiol-042022-020923 | url = }}</ref><ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = }}</ref> 4-desmethylene-LSD has been found to produce psychoplastogenic effects on neurite growth ''in vitro''.<ref name="WO2021076572" />

Many serotonin 5-HT2A receptor agonists, for instance LSD, produce psychedelic effects in humans.<ref name="WO2021076572" /><ref name="Nichols2018">{{cite journal | vauthors = Nichols DE | title = Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2331–2343 | date = October 2018 | pmid = 29461039 | doi = 10.1021/acschemneuro.8b00043 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-LSD.pdf}}</ref><ref name="Halberstadt2015">{{cite journal | vauthors = Halberstadt AL | title = Recent advances in the neuropsychopharmacology of serotonergic hallucinogens | journal = Behav Brain Res | volume = 277 | issue = | pages = 99–120 | date = January 2015 | pmid = 25036425 | doi = 10.1016/j.bbr.2014.07.016 | url = | pmc = 4642895 }}</ref><ref name="KwanOlsonPreller2022">{{cite journal | vauthors = Kwan AC, Olson DE, Preller KH, Roth BL | title = The neural basis of psychedelic action | journal = Nat Neurosci | volume = 25 | issue = 11 | pages = 1407–1419 | date = November 2022 | pmid = 36280799 | pmc = 9641582 | doi = 10.1038/s41593-022-01177-4 | url = https://alexkwanlab.org/wp-content/uploads/2022/11/kwanNatNeurosci2022.pdf}}</ref> The publication that reported 4-desmethylene-LSD specifically pertained to psychoplastogenic ergoline-like compounds with no or reduced hallucinogenic activity for potential therapeutic use.<ref name="WO2021076572" /> However, the hallucinogenic-related properties of 4-desmethylene-LSD and the other reported compounds, for instance their effects in the head-twitch response (HTR) assay, were not individually described.<ref name="WO2021076572" /> As such, it remains unclear whether or not 4-desmethylene-LSD could have psychedelic effects in humans.<ref name="WO2021076572" />

==Chemistry== ===Related compounds=== Other related compounds in which one or more other carbons have been removed from the LSD's ergoline ring system to produce simplified and less-rigid phenethylamines and tryptamines include ''N''-DEAOP-NMT (desvinyl-LSD)<ref name="Nichols1973">{{cite thesis | vauthors = Nichols DE | title = Potential Psychotomimetics: Bromomethoxyamphetamines and Structural Congeners of Lysergic Acid | date = May 1973 | publisher = University of Iowa | pages = 23 | oclc = 1194694085 | url = https://bitnest.netfirms.com/external/Theses/Nichols1973#page=32 | quote = Sklar, et al. (53) found the diethylacrylamide adduct 20 to be approximately 1/10 as active as LSD in mice, although Norris and Blicke (54) reported 21 to have little oxytocic activity. [...] 20 = R = C2H5. 21 = R = CH3 [...]}}</ref><ref name="NorrisBlicke1952">{{cite journal | vauthors = Norris PE, Blicke FF | title = Potential ergot substitutes: esters and amides of beta-amino acids | journal = Journal of the American Pharmaceutical Association (Scientific Ed.) | volume = 41 | issue = 12 | pages = 637–639 | date = December 1952 | pmid = 13022416 | doi = 10.1002/jps.3030411204 | url = | quote = Six esters and amides of derivatives of β-alanine which are related to lysergic acid have been prepared and tested for oxytocic activity. None of these products possess a significant oxytocic activity. [...] The purpose of this investigation was to synthesize amides and also esters of compounds (II–V) which represent fragments of the lysergic acid molecule in the hope that some of these products might possess oxytocic activity. Various modified fragments of the lysergic acid molecule have been synthesized previously; it was claimed that some of the compounds are active oxytocics (1—7). [...] Pharmacologic data indicated that none of the esters or amides of compounds II—V which were prepared possess a significant oxytocic action when compared to the clinically used oxytocics. However, the diethylamide of N-methyl-N-[β′-(3-indolyl)-ethyl]-β-alanine (IIIc) appeared to have an oxytocic activity approximately ten times stronger than that of the diethylamide of N-methyl-N-(β′-phenethyl)-β-alanine (IIc).}}</ref> and NDTDI (9-desmethine-LSD).<ref name="EuropeanProjectResponse2017">{{citation | title = Analytical Report NDTDI (C19H27N3O) 3-({2-azatricyclo[6.3.1.0⁴,¹²]dodeca-1(11),3,8(12),9-tetraen-6-yl}(methyl)amino)-N,N-diethylpropanamide | publisher = European Project Response | url = https://www.policija.si/apps/nfl_response_web/0_Analytical_Reports_final/NDTDI-ID-1737-16_report.pdf}}</ref><ref name="Likumi2017">{{cite web | author=Autorizēties savā kontā | title=Par aizlieguma noteikšanu vielai NDTDI un tās saturošiem izstrādājumiem | trans-title=On the prohibition of the substance NDTDI and products containing it | website=LIKUMI.LV | date=March 2017 | url=https://likumi.lv/ta/id/289200 | language=lv | access-date=20 March 2025}}</ref><ref name="PubChem-NDTDI">{{cite web | title=N,N-Diethyl-N3-methyl-N3-(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)-I(2)-alaninamide | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/163192742 | access-date=20 March 2025}}</ref> Desvinyl-LSD is the analogue of LSD in which the carbon atoms at positions 9 and 10 of the ergoline ring system have been removed to make a fully non-rigid tryptamine,<ref name="Nichols1973" /><ref name="NorrisBlicke1952" /> while 9-desmethine is the analogue of LSD in which the methine at position 9 has been removed to make a rigid tricyclic tryptamine.<ref name="EuropeanProjectResponse2017" /><ref name="Likumi2017" /><ref name="PubChem-NDTDI" /> Desvinyl-LSD has been found to produce LSD-like effects in rodents,<ref name="Nichols1973" /><ref name="NorrisBlicke1952" /> while 9-desmethine-LSD has been encountered as a novel recreational and designer drug and made illegal in parts of Europe.<ref name="EuropeanProjectResponse2017" /><ref name="Likumi2017" />

The analogue of 4-desmethylene-LSD without the ethyl groups on the amide has been described.<ref name="Nichols1973" /><ref name="JuliaIgolenKolb1971">{{cite journal | vauthors = Julia M, Igolen J, Kolb A | title = Preparation de quelques phenyl et indolyl-5-tetrahydro-1.2.3.6 nicotinamides | trans-title = Preparation of some phenyl and indol-5-yl-1,2,3,6-tetrahydronicotinamides | journal = Comptes Rendus de l'Académie des Sciences, Série C | date = 20 December 1971 | volume = 273 | issue = 25 | pages = 1776–1777 | url = https://scholar.google.com/scholar?q=%22PREPARATION+OF+SOME+PHENYL+AND+INDOL-5-YL+1%2C+2%2C+3%2C+6-TETRAHYDRONICOTINAMIDES%22 | archive-url = https://web.archive.org/web/20210202000000/https://scholar.google.com/scholar?q=%22PREPARATION+OF+SOME+PHENYL+AND+INDOL-5-YL+1%2C+2%2C+3%2C+6-TETRAHYDRONICOTINAMIDES%22 | archive-date = 2 February 2021}} [https://archive.org/details/cr-268/CR_273/page/1776/mode/1up Alt URL]</ref> In addition, 4-desmethylene-LSD's analogue without the amide ethyl groups and with a phenyl ring instead of the indole ring has been described.<ref name="Nichols1973" /><ref name="JuliaIgolenKolb1971" /> Their activities were not reported.<ref name="Nichols1973" /><ref name="JuliaIgolenKolb1971" />

WXVL_BT0793LQ2118, an analogue of 4-desmethylene-LSD lacking the ''N'',''N''-diethyl-carboxamide moiety and with a fluorine at the 6-position, has been reported.<ref name="LyuKapolkaGumpper2024">{{cite bioRxiv | vauthors = Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, Barros-Álvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Tummino TA, Huang S, Irwin JJ, Tarkhanova OO, Moroz Y, Skiniotis G, Kruse AC, Shoichet BK, Roth BL | title = AlphaFold2 structures template ligand discovery | date = March 2024 | biorxiv = 10.1101/2023.12.20.572662}}</ref><ref name="PubChem-WXVL_BT0793LQ2118">{{cite web | title=6-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1H-indole | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/171676435 | access-date=21 March 2025}}</ref> It was identified via ''in silico'' screening of 1.6{{nbsp}}billion molecules for serotonin 5-HT2A receptor agonism with AlphaFold2.<ref name="LyuKapolkaGumpper2024" /> Following identification, the drug was assessed and found to be a potent serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist.<ref name="LyuKapolkaGumpper2024" />

==History== 4-Desmethylene-LSD was first described in the literature by 2021.<ref name="WO2021076572" /> It has been patented by Delix Therapeutics.<ref name="WO2021076572" />

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/13055 DEIMPCA - Isomer Design]

{{DEFAULTSORT:Desmethylene-LSD, 4-}} Category:5-HT2A agonists Category:5-HT2C agonists Category:Carboxamides Category:Diethylamino compounds Category:Experimental drugs Category:Indoles Category:Methyl compounds Category:Partial ergolines Category:Psychoplastogens Category:Serotonin receptor agonists Category:Tetrahydropyridines