TGF-8027

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TGF-8027
TGF-8027 structure.png
Clinical data
Other namesTGF8027; TGF-8-027; N-[1-(2-Hydroxyphenyl)ethyl]-2,5-dimethoxy-4-cyanophenethylamine
Drug class Selective serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Chemical and physical data
Formula C19H22N2O3
Molar mass 326.396 g·mol−1
3D model (JSmol)
  • C1=C(C#N)C(OC)=CC(CCN([H])C(C)C2=CC=CC=C2O[H])=C1OC
  • InChI=1S/C19H22N2O3/c1-13(16-6-4-5-7-17(16)22)21-9-8-14-10-19(24-3)15(12-20)11-18(14)23-2/h4-7,10-11,13,21-22H,8-9H2,1-3H3
  • Key:YGVDYCKUVCKBFS-UHFFFAOYSA-N

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]

Contents

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 Tooltip half-maximal effective concentration and Emax Tooltip maximal efficacy 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 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, et al. (September 2025). "Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design". J Med Chem acs.jmedchem.5c01855. doi:10.1021/acs.jmedchem.5c01855. PMID   40997862.


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