Chemistry:TGF-8027

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TGF-8027, or TGF-8-027, also known as N-[1-(2-hydroxyphenyl)ethyl]-2,5-dimethoxy-4-cyanophenethylamine, is a highly selective serotonin 5-HT2A receptor agonist and putative serotonergic psychedelic of the phenethylamine, 2C, and 25-NB (NBOH) families.[1] It is one of the most selective serotonin 5-HT2A receptor agonists known and shows much greater selectivity than earlier agents like 25CN-NBOH, DMBMPP, and LPH-5.[1] The drug produces psychedelic-like effects in rodents and hence may be hallucinogenic in humans.[1] TGF-8027 was first described in the literature in 2025.[1]

Interactions

Pharmacology

Pharmacodynamics

TGF-8027 acts as a highly selective serotonin 5-HT2A receptor full agonist.[1] Its affinities (Ki) were 7.4 nM at the serotonin 5-HT2A receptor, 390 nM at the serotonin 5-HT2B receptor, and 1,100 nM at the serotonin 5-HT2C receptor.[1] The drug's EC50 and Emax values in terms of Gq dissociation were 3.3 nM (91%) at the human serotonin 5-HT2A receptor, 7,600 nM (45%) at the human serotonin 5-HT2B receptor, and 160 nM (123%) at the human serotonin 5-HT2C receptor.[1] It was also assessed at these receptors with other assays.[1] In addition, TGF-8027 was screened at a large panel of other targets, including receptors and transporters, and showed relatively little affinity at these sites.[1]

With regard to selectivity for the human serotonin 5-HT2A receptor over the human serotonin 5-HT2C receptor, TGF-8027 showed 149-fold selectivity in terms of affinity, 48.5-fold selectivity in terms of Gq dissociation, 84.5-fold selectivity in terms of calcium flux, and 2,450-fold selectivity in terms of IP1 accumulation.[1] It is far more selective as an agonist of the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor than previous selective serotonin 5-HT2A receptor agonists such as 25CN-NBOH, DMBMPP, and rac-LPH-5 (fold selectivity for Gq dissociation in the same study of 10.0, 13.5, and 4.4, respectively).[1] Previous research had not rigorously assessed the selectivity of these earlier compounds via employment of multiple selectivity assays.[1]

TGF-8027 was less selective for the mouse serotonin 5-HT2A receptor over the mouse serotonin 5-HT2C receptor, but still showed about 15-fold selectivity for the former over the latter in terms of Gq dissociation.[1] In accordance with its serotonin 5-HT2A receptor activation, the drug robustly induces the head-twitch response, a behavioral proxy of psychedelic effects, in mice.[1] As such, it would be expected to produce psychedelic effects in humans.[1]

The compound is a racemic mixture of (+)- and (–)-enantiomers, with the (–)-enantiomer being a more potent serotonin 5-HT2A receptor agonist but the (+)-enantiomer being more selective for activation of the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor.[1]

Chemistry

TGF-8027, also known as N-[1-(2-hydroxyphenyl)ethyl]-2,5-dimethoxy-4-cyanophenethylamine, is a substituted phenethylamine and a 2C and 25-NB (NBOH) derivative.[1] It is specifically the derivative of 25CN-NBOH in which the benzyl group has been α-methylated.[1] The compound is a racemic mixture of (+)- and (–)-enantiomers.[1] A series of other analogues of TGF-8027 have also been reported, some of which show further improved serotonin 5-HT2A receptor selectivity relative to TGF-8027 itself.[1]

History

TGF-8027 was first described in the scientific literature by Tyler Fenske and colleagues in 2025.[1] The group also included Adam Halberstadt.[1] The serotonin 5-HT2A and 5-HT2C receptors show considerable homology, which has made development of selective serotonin 5-HT2A receptor agonists difficult.[1] TGF-8027 was discovered via a rational structure-guided design that took advantage of an identified single-residue difference between the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor in transmembrane 2 (TM2) of the extended binding pocket.[1] The group also reported a series of other selective serotonin 5-HT2A receptor agonists in addition to TGF-8027, some of which showed even further improved selectivity.[1] TGF-8027 was selected for more in-depth characterization over other compounds, for instance in the head-twitch response assay, because it showed among the highest selectivity and potency at the mouse serotonin 5-HT2A receptor in addition to the human serotonin 5-HT2A receptor.[1]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 "Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design". J Med Chem. September 2025. doi:10.1021/acs.jmedchem.5c01855. PMID 40997862. 


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