F (psychedelic)

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F
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Clinical data
Other namesF-1; 5-Methoxy-6-(2-Aminopropyl)-2,3-dihydrobenzofuran; 5-Methoxy-6-APDB; 5-MeO-6-APDB; 6-Methoxy-4-desoxy-MDA
Drug class Putative serotonergic psychedelic or hallucinogen
ATC code
  • None
Identifiers
  • 1-(5-methoxy-2,3-dihydro-1-benzofuran-6-yl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C12H17NO2
Molar mass 207.273 g·mol−1
3D model (JSmol)
  • CC(CC1=C(C=C2CCOC2=C1)OC)N
  • InChI=1S/C12H17NO2/c1-8(13)5-10-7-12-9(3-4-15-12)6-11(10)14-2/h6-8H,3-5,13H2,1-2H3
  • Key:IUKWXRPAJLVHHN-UHFFFAOYSA-N

F, or F-1, also known as 5-methoxy-6-(2-aminopropyl)-2,3-dihydrobenzofuran (5-methoxy-6-APDB), is a putative psychedelic drug of the phenethylamine, DOx, and benzofuran families. [1] [2] [3] [4] [5] It is the derivative of 2,5-dimethoxyamphetamine (2,5-DMA or DOH) in which the 5-methoxy group on the benzene ring has been cyclized into a tetrahydrofuran ring tethered at the 4 position. [1] It is also an analogue of DOH-5-hemiFLY, but in contrast to DOH-5-hemiFLY, F has the 5-methoxy group tethered at the 4 position rather than at the 6 position. [1] While related to them, F is not a FLY compound as its tetrahydrofuran ring is attached at different positions than FLY series compounds. [3]

Contents

Use and effects

According to Alexander Shulgin in 2011, the effects of F in humans are unknown. [1] However, David E. Nichols reported in 1981, via personal communication with Shulgin and M. Trampota in 1980, that F was "shown to possess clinical activity". [6] On the other hand, Shulgin reported in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved) that F was inactive at doses of up to 30 mg. [7] [2]

Interactions

Pharmacology

Pharmacodynamics

F showed an affinity (Ki) of 388 nM for the serotonin 5-HT2 receptor, which was 21-fold lower than that of DOM. [3] [8] [2] It fully substituted for LSD in rodent drug discrimination tests, albeit with about 14-fold lower potency than DOM. [1] [3] [4] [9] [8] [2] In subsequent publications by the same research group, it was said that F failed to show LSD-like activity, was "nearly inactive in an in vivo behavioral assay for hallucinogen-like activity in rats", or had "dramatically attenuated LSD-like behavioral effects in rats". [10] [11] [12] [5]

Chemistry

Derivatives

Derivatives of F, including F-2 and F-22, are known. [7] [1] They were described by Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). [7] [1] These compounds feature one or two methyl groups at the distal position of the attached tetrahydrofuran ring. [7] [1] Both compounds were inactive as psychedelic drugs at the assessed doses in humans. [7] [1] F was 3-fold more potent than F-2 in animal studies. [7]

History

F was first described in the scientific literature by David E. Nichols and colleagues by 1981. [1] [6] It was briefly described by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved) [7] and was included as an entry in Shulgin's 2011 book The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . [1]

Society and culture

The drug was not an explicitly controlled substance in the United States as of 2011. [1]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Shulgin A, Manning T, Daley PF (2011). "#66. F". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley, CA: Transform Press. pp. 137–138. ISBN   978-0-9630096-3-0. OCLC   709667010.
  2. 1 2 3 4 Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 495–497, 503, 828–829, 851–852, 860. ISBN   978-3-03788-700-4. OCLC   858805226.
  3. 1 2 3 4 Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT 2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi: 10.1002/wmts.42 . ISSN   2190-460X. When the 5-methoxy of DOM (39) was 'tethered' to the 4-position, as in 47, the activity was reduced nearly 20-fold compared to DOM in drug discrimination tasks.81 By contrast, when the 5-methoxy was tethered to the 6-position, compound 48 was as at least as potent as DOM.82 These studies seemed to indicate clearly that the electrons of the methoxy oxygen should be oriented in a particular direction for optimal receptor interaction. Affinity for the [125I]DOI-labeled receptor in rat prefrontal cortex paralleled these findings, with an affinity for 47 of 488 nM and for 48 of 3.1 nM (Figure 20).
  4. 1 2 Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN   978-3-662-55878-2. PMID   28401524. The need for the 2- and 5-oxygen substituents in the phenethylamine hallucinogens raises the question as to what role they may be playing. The most compelling hypothesis is that they serve as hydrogen bond acceptors in the orthosteric ligand binding site. If true, there should then be a dependence on the oxygen unshared electron pair orientations. "Tethering" the 5-methoxy of DOM (37) to the 4-position, leading to compound 49, reduced activity nearly 20-fold in an in vivo rat drug discrimination assay, compared to DOM. (Nichols et al. 1986) When the 5-methoxy of DOB was tethered to the 6-position, however, compound 50 was as potent as DOM (Nichols et al. 1991).
  5. 1 2 Blaazer AR, Smid P, Kruse CG (September 2008). "Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors". ChemMedChem. 3 (9): 1299–1309. doi:10.1002/cmdc.200800133. PMID   18666267. Incorporation of methoxy substituents into rigid ring structures in phenylalkylamine has been used to investigate the active binding orientation of these substituents; restricting the ligand flexibility of DOM (15) through the synthesis of 2,3-dihydrobenzofuran analogues showed that the LSD-like activity was greatly reduced when the oxygen lone pair of the 5-methoxy group was directed syn to the alkylamine chain (dihydrofuran 34).[183] Another possible explanation for the diminished LSD-like activity is unfavorable steric interactions between the ring structure and the binding site.
  6. 1 2 Nichols DE (August 1981). "Structure-activity relationships of phenethylamine hallucinogens". Journal of Pharmaceutical Sciences. 70 (8): 839–849. Bibcode:1981JPhmS..70..839N. doi:10.1002/jps.2600700802. PMID   7031221.
  7. 1 2 3 4 5 6 7 Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN   0-9630096-0-5. OCLC   25627628. "The plain furan analogue, without any methyl groups on it, has been made. [...] In the rat studies, it was three times more potent than F-2, but still some 15 times less potent than DOM. And in initial human trials (of up to 30 milligrams) there were again no effects noted. Naming of this material is easy chemically (6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran) but tricky as to code. If the numbers that follow the “F” give the location of the methyl groups, then this material, without any such groups, can have no numbers following, and should properly be simply “F.” OK, it is “F.”"
  8. 1 2 Nichols DE, Snyder SE, Oberlender R, Johnson MP, Huang XM (January 1991). "2,3-Dihydrobenzofuran analogues of hallucinogenic phenethylamines". Journal of Medicinal Chemistry. 34 (1): 276–281. doi:10.1021/jm00105a043. PMID   1992127.
  9. ↑ Nichols DE, Hoffman AJ, Oberlender RA, Riggs RM (February 1986). "Synthesis and evaluation of 2,3-dihydrobenzofuran analogues of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: drug discrimination studies in rats". Journal of Medicinal Chemistry. 29 (2): 302–304. doi:10.1021/jm00152a022. PMID   3950910.
  10. ↑ Nichols DE (1994). "Medicinal Chemistry and Structure-Activity Relationships". In Cho AK, Segal DS (eds.). Amphetamine and Its Analogs: Psychopharmacology, Toxicology, and Abuse. Academic Press. pp. 3–41. ISBN   978-0-12-173375-9. Over the years, much attention has focused on the reasons for the importance of the 4 substituent in this series. Researchers have suggested that this moiety may force the 5-methoxy group to adopt an "anti" orientation (Nichols et al., 1986b). For example, the 2,3-dihydrobenzofuran-6-yl compounds 31 and 32 have been shown to lack LSD-like activity, whereas the dihydrobenzofuran-4-yl compound 33 is as potent as its flexible 5-methoxy analog DOB (Table 1; Nichols et at., 1991c). These studies clearly show that the preferred orientation of the 5-methoxy group is anti with respect to the 4 substituent.
  11. ↑ Monte AP, Marona-Lewicka D, Cozzi NV, Nelson DL, Nichols DE (1995). "Conformationally Restricted Tetrahydro-1-Benzoxepin Analogs of Hallucinogenic Phenethylamines". Medicinal Chemistry Research. 5 (651–663).
  12. ↑ Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, Nichols DE (July 1996). "Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups". Journal of Medicinal Chemistry. 39 (15): 2953–2961. doi:10.1021/jm960199j. PMID   8709129.
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