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| Other names | F-1; Semi-fly; Semi-FLY |
| Drug class | Putativeserotonergic psychedelic orhallucinogen |
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| Formula | C12H17NO2 |
| Molar mass | 207.273 g·mol−1 |
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F, orF-1, also known assemi-fly, is a putativepsychedelic drug of thephenethylamine,DOx, andbenzofuran families.[1][2][3][4][5] It is thederivative of2,5-dimethoxyamphetamine (2,5-DMA or DOH) in which the 5-methoxygroup on thebenzenering has beencyclized into atetrahydrofuran ring tethered at the 4 position.[1] It is also ananalogue ofDOH-FLY (FLY), but in contrast to F, DOH-FLY has the 5-methoxy group tethered at the 6 position and the 2-methoxy group has additionally been cyclized and tethered to the 3 position.[1] Despite the moniker "semi-fly", F is not technically aFLY compound as its tetrahydrofuran ring is attached at different positions than FLY series compounds.[3]
According toAlexander 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 bookPiHKAL (Phenethylamines I Have Known and Loved) that F was inactive at doses of up to 30 mg.[7]
F showed anaffinity (Ki) of 388 nM for theserotonin5-HT2 receptor, which was 21-fold lower than that ofDOM.[3][8] It fully substituted forLSD in rodentdrug discrimination tests, albeit with about 14-fold lowerpotency than DOM.[1][3][4][9][8] 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]
F was first described in thescientific literature byDavid E. Nichols and colleagues by 1981.[1][6] It was briefly described byAlexander Shulgin in his 1991 bookPiHKAL (Phenethylamines I Have Known and Loved)[7] and was included as an entry in Shulgin's 2011 bookThe Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds.[1]
The drug was not an explicitlycontrolled substance in theUnited States as of 2011.[1]
Derivatives of F, includingF-2 andF-22, are known.[7][1] They were described by Shulgin in his 1991 bookPiHKAL (Phenethylamines I Have Known and Loved).[7][1] These compounds feature one or twomethyl groups at the distal position of the attachedtetrahydrofuranring.[7][1] Both compounds were inactive as psychedelic drugs at the assessed doses in humans.[7][1] F was 3-fold morepotent than F-2 inanimal studies.[7]
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).
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).
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.
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.