TGF-8027

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-HT_2A receptor agonist and putative serotonergic psychedelic of the phenethylamine, 2C, and 25-NB (NBOH) families. It is one of the most selective serotonin 5-HT_2A receptor agonists known and shows much greater selectivity than earlier agents like 25CN-NBOH, DMBMPP, and LPH-5. The drug produces psychedelic-like effects in rodents and hence may be hallucinogenic in humans. TGF-8027 was first described in the literature in 2025.

Interactions

Pharmacology

Pharmacodynamics

TGF-8027 acts as a highly selective serotonin 5-HT_2A receptor full agonist. Its affinities (K_i) were 7.4nM at the serotonin 5-HT_2A receptor, 390nM at the serotonin 5-HT_2B receptor, and 1,100nM at the serotonin 5-HT_2C receptor. The drug's and values in terms of G_q dissociation were 3.3nM (91%) at the human serotonin 5-HT_2A receptor, 7,600nM (45%) at the human serotonin 5-HT_2B receptor, and 160nM (123%) at the human serotonin 5-HT_2C receptor. It was also assessed at these receptors with other assays. 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.

With regard to selectivity for the human serotonin 5-HT_2A receptor over the human serotonin 5-HT_2C receptor, TGF-8027 showed 149-fold selectivity in terms of affinity, 48.5-fold selectivity in terms of G_q dissociation, 84.5-fold selectivity in terms of calcium flux, and 2,450-fold selectivity in terms of IP1 accumulation. It is far more selective as an agonist of the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor than previous selective serotonin 5-HT_2A receptor agonists such as 25CN-NBOH, DMBMPP, and rac-LPH-5 (fold selectivity for G_q dissociation in the same study of 10.0, 13.5, and 4.4, respectively). Previous research had not rigorously assessed the selectivity of these earlier compounds via employment of multiple selectivity assays.

TGF-8027 was less selective for the mouse serotonin 5-HT_2A receptor over the mouse serotonin 5-HT_2C receptor, but still showed about 15-fold selectivity for the former over the latter in terms of G_q dissociation. In accordance with its serotonin 5-HT_2A receptor activation, the drug robustly induces the head-twitch response, a behavioral proxy of psychedelic effects, in mice. As such, it would be expected to produce psychedelic effects in humans.

The compound is a racemic mixture of (+)- and (–)-enantiomers, with the (–)-enantiomer being a more potent serotonin 5-HT_2A receptor agonist but the (+)-enantiomer being more selective for activation of the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor.

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. It is specifically the derivative of 25CN-NBOH in which the benzyl group has been α-methylated. The compound is a racemic mixture of (+)- and (–)-enantiomers. A series of other analogues of TGF-8027 have also been reported, some of which show further improved serotonin 5-HT_2A receptor selectivity relative to TGF-8027 itself.

History

TGF-8027 was first described in the scientific literature by John McCorvy's lab and colleagues in 2025. The group also included Adam Halberstadt. The serotonin 5-HT_2A and 5-HT_2C receptors show considerable homology, which has made development of selective serotonin 5-HT_2A receptor agonists difficult. TGF-8027 was discovered via a rational structure-guided design that took advantage of an identified single-residue difference between the serotonin 5-HT_2A receptor and the serotonin 5-HT_2C receptor in transmembrane 2 (TM2) of the extended binding pocket. The group also reported a series of other selective serotonin 5-HT_2A receptor agonists in addition to TGF-8027, some of which showed even further improved selectivity. 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-HT_2A receptor in addition to the human serotonin 5-HT_2A receptor.

Society and culture

Legal status

Canada

TGF-8027 may be a controlled substance in Canada under phenethylamine blanket-ban language.

United States

TGF-8027 is not an explicitly controlled substance in the United States. However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

See also

• 25-NB
• 25CN-NBOH
• 2C-CN
• DOCN

References

External links

• TGF-8027 - Isomer Design