Mescaline-FLY

{{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | drug_name = | image = Mescaline-FLY.svg | image_class = skin-invert-image | width = 235px | caption =

| legal_status =

| IUPAC_name = 2-(8-methoxy-2,3,5,6-tetrahydrofuro[3,2-f][1]benzofuran-4-yl)ethanamine | C=13 | H=17 | N=1 | O=3 | SMILES = COC1=C2C(=C(C3=C1OCC3)CCN)CCO2 | StdInChI = 1S/C13H17NO3/c1-15-13-11-9(3-6-16-11)8(2-5-14)10-4-7-17-12(10)13/h2-7,14H2,1H3 | StdInChIKey = NZPLNCQAEYLYII-UHFFFAOYSA-N }}

'''Mescaline-FLY''', also known as '''flyscaline''', '''M-FLY''', or '''MeO-2C-2,6-IFLY''', is a putatively non-hallucinogenic serotonin receptor modulator of the phenethylamine, scaline, and FLY families.<ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter = #68. FLY | pages = 141–143 | chapter-url = https://archive.org/details/shulgin-index-vol-1/page/141/mode/1up | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher = Transform Press | location = Berkeley, CA | volume = 1 | year = 2011 | isbn = 978-0-9630096-3-0 | oclc = 709667010 | quote = }}</ref><ref name="TrachselLehmannEnzensperger2013">{{cite book | vauthors = Trachsel D, Lehmann D, Enzensperger C | title = Phenethylamine: von der Struktur zur Funktion | location = Solothurn | pages = 700–701, 721 | year = 2013 | trans-title = Phenethylamines: From Structure to Function | edition = 1 | publisher = Nachtschatten-Verlag | series = Nachtschatten-Science | isbn = 978-3-03788-700-4 | oclc = 858805226 | url = https://books.google.com/books?id=-Us1kgEACAAJ | language = de }}</ref><ref name="MonteWaldmanMarona-Lewicka1997">{{cite journal | vauthors = Monte AP, Waldman SR, Marona-Lewicka D, Wainscott DB, Nelson DL, Sanders-Bush E, Nichols DE | title = Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives | journal = J Med Chem | volume = 40 | issue = 19 | pages = 2997–3008 | date = September 1997 | pmid = 9301661 | doi = 10.1021/jm970219x | url = }}</ref><ref name="Monte1995">{{cite thesis | vauthors = Monte AP | title=Structure-activity relationships of hallucinogens: Design, synthesis, and pharmacological evaluation of a series of conformationally restricted phenethylamines | website=Purdue e-Pubs | date=1995 | url=https://docs.lib.purdue.edu/dissertations/AAI9601547/ | archive-url=https://bitnest.netfirms.com/external/Theses/Monte1995 | archive-date=16 June 2025}}</ref> It is the FLY (benzodifuran) analogue of the psychedelic drug mescaline.<ref name="ShulginManningDaley2011" /><ref name="TrachselLehmannEnzensperger2013" /><ref name="MonteWaldmanMarona-Lewicka1997" /><ref name="Monte1995" />

==Use and effects== Mescaline-FLY is not known to have been tested in humans, and hence it is unknown whether it produces psychedelic effects in humans.<ref name="ShulginManningDaley2011" /> However, based on its lack of psychedelic-like effects in animals, it may not be expected to be hallucinogenic in humans.<ref name="MonteWaldmanMarona-Lewicka1997" /><ref name="Monte1995" />

==Pharmacology== ===Pharmacodynamics=== Mescaline-FLY shows affinity for the serotonin 5-HT2 receptors.<ref name="MonteWaldmanMarona-Lewicka1997" /> Its affinities (Ki) were 335 to 4,443{{nbsp}}nM for the serotonin 5-HT2A receptor, 205 to 302{{nbsp}}nM for the serotonin 5-HT2B receptor, and 61.5 to 654{{nbsp}}nM for the serotonin 5-HT2C receptor.<ref name="MonteWaldmanMarona-Lewicka1997" /> The affinity of mescaline-FLY for the serotonin 5-HT2A receptor was only slightly higher than that of mescaline, whereas it showed several-fold higher affinity for the serotonin 5-HT2C receptor and about 2-fold higher affinity for the serotonin 5-HT2B receptor compared to mescaline.<ref name="MonteWaldmanMarona-Lewicka1997" /> In a subsequent study, at the serotonin 5-HT2A receptor, its affinity (K0.5) was 243{{nbsp}}nM and its {{Abbrlink|EC50|half-maximal effective concentration}} ({{Abbrlink|Emax|maximal efficacy}}) was 3,470{{nbsp}}nM (57%), relative to respective values for mescaline of 801{{nbsp}}nM and 2,700{{nbsp}}nM (88%).<ref name="McCorvy2013">{{cite thesis | vauthors = McCorvy JD | title = Mapping the binding site of the 5-HT2A receptor using mutagenesis and ligand libraries: Insights into the molecular actions of psychedelics | date = 16 January 2013 | degree = Ph.D. | publisher = Purdue University | via = Purdue e-Pubs | url = https://docs.lib.purdue.edu/dissertations/AAI3545320/ | archive-url = https://bitnest.netfirms.com/external/Theses/McCorvey2012 | archive-date = 25 March 2025 }}</ref> Hence, whereas mescaline is a full agonist of the serotonin 5-HT2A receptor, mescaline-FLY is a moderate-efficacy partial agonist of the receptor.<ref name="McCorvy2013" />

The drug failed to substitute for LSD in rodent drug discrimination tests, producing a maximum substitution of 29% at a dose of 55.2{{nbsp}}μmol/kg, whereas mescaline fully substituted for LSD with an {{Abbrlink|ED50|median effective dose}} of 33.5{{nbsp}}μmol/kg.<ref name="MonteWaldmanMarona-Lewicka1997" /><ref name="Monte1995" /><ref name="Nichols2012">{{cite journal | vauthors = Nichols DE | title = Structure–activity relationships of serotonin 5-HT2A agonists | journal = Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | volume = 1 | issue = 5 | pages = 559–579 | date = 2012 | doi = 10.1002/wmts.42 | issn = 2190-460X | doi-access = free | quote = Surprisingly, however, when this strategy was applied to mescaline analogs, activity of the tethered compounds was reduced. The mono furanyl compound 56 lost efficacy and mescaline-like potency in a rat behavioral model, and the difuranyl compound 57 suffered a further decrease in the activity.88 It was speculated that for 3,4,5-substituted compounds, perhaps the methoxy groups needed to be freely rotating in order to achieve the active binding orientation. In any event, these divergent results support the idea that the binding pose of 2,4,5-substituted compounds differs from that of 3,4,5-substituted compounds (Figure 23). [...] FIGURE 23 <nowiki>|</nowiki> Mescaline analogs with constrained methoxy groups. [...]}}</ref><ref name="Nichols2018">{{cite book | vauthors = Nichols DE | chapter = Chemistry and Structure-Activity Relationships of Psychedelics | title = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = https://bitnest.netfirms.com/external/10.1007/7854_2017_475 | quote = When this strategy was applied to 3,4,5-substituted mescaline analogues, however, activity of the tethered compounds was reduced. Although affinity at the 5-HT2A receptor increased compared to mescaline, the monocyclic furano compound 58 lost both efficacy and mescaline-like potency in a rat behavioral model, and difuranyl compound 59 was even less active (Monte et al. 1997). These divergent results suggest that the binding pose of 2,4,5-substituted compounds differs from that of 3,4,5-substituted compounds. Mutagenesis studies support that conclusion, as mutations of polar residues in the orthosteric binding site of the human 5-HT2A receptor have different effects, depending on whether the ligand being examined is a 2,4,5- or a 3,4,5-substituted molecule (McCorvy 2012). [...]}}</ref><ref name="CasselsSáez-Briones2018">{{cite journal | vauthors = Cassels BK, Sáez-Briones P | title = Dark Classics in Chemical Neuroscience: Mescaline | journal = ACS Chemical Neuroscience | volume = 9 | issue = 10 | pages = 2448–2458 | date = October 2018 | pmid = 29847089 | doi = 10.1021/acschemneuro.8b00215 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-MESCALINE.pdf | quote = The result of tethering the C-3 methoxyl group or both the C-3 and C-5 groups of the isopropylamine analogue of mescaline (TMA) forming dihydrofuran rings was somewhat disappointing.131 In the 2,5-dimethoxy-4-X series, this modification had led to more potent derivatives, which was explained by the favorable orientation of the oxygen lone pairs for hydrogen bonding with serine residues in the 5-HT2A receptor’s active site.132,133 In the case of the 3,4,5- trioxygenated compounds, binding studies at 5-HT2A and 5-HT2C receptors revealed somewhat higher affinities than mescaline but, in phosphoinositide hydrolysis assays (only for 5-HT2A), lower efficacies relative to serotonin and the full agonist mescaline (60 and 45%, respectively). More striking, however, was the observation that the new compounds did not fully substitute for LSD in LSD-trained rats, and at doses well above the mescaline EC50, only 50 and 29% appropriate responding was recorded. In view of this unexpected result, 3,5- dimethoxy-4-ethoxyphenethylamine (escaline), which is considerably more potent than mescaline in humans,128 was also tested. It was found to have about twice the affinity of mescaline for 5-HT2A receptors and was a complete agonist with very similar functional potency, but again it failed to substitute completely for LSD in the drug discrimination experiments. [...] Figure 2. Mescaline and conformationally restricted analogues. [...]}}</ref> The lack of substitution with mescaline-FLY is in notable contrast to findings with other FLY drugs, such as 2C-B-FLY, DOB-FLY, and Bromo-DragonFLY.<ref name="Nichols2012" /><ref name="Nichols2018" /><ref name="CasselsSáez-Briones2018" /><ref name="MonteMarona-LewickaParker1996">{{cite journal | vauthors = Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, Nichols DE | title = Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups | journal = J Med Chem | volume = 39 | issue = 15 | pages = 2953–2961 | date = July 1996 | pmid = 8709129 | doi = 10.1021/jm960199j | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=be8b98f51cdae9258536c6efa357b80bb22d64f1}}</ref>

==History== Mescaline-FLY was first described in the scientific literature by the lab of David E. Nichols and colleagues by 1995.<ref name="MonteWaldmanMarona-Lewicka1997" /><ref name="Monte1995" />

==Society and culture== ===Legal status=== ====Canada==== Mescaline-FLY is not a controlled substance in Canada as of 2025.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

====United States==== Mescaline-FLY is not an explicitly controlled substance in the United States.<ref name="OrangeBook2026">{{citation | title = Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) | date = January 2026 | publisher = U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division | location = United States | url = https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf}}</ref> However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/2039 Mescaline-FLY - Isomer Design]

Category:David E. Nichols Category:Dihydrofurans Category:FLY (psychedelics) Category:Non-hallucinogenic 5-HT2A receptor agonists Category:Scalines Category:Serotonin receptor modulators