TGF-8027, orTGF-8-027, also known asN-[1-(2-hydroxyphenyl)ethyl]-2,5-dimethoxy-4-cyanophenethylamine, is a highlyselectiveserotonin5-HT2A receptoragonist and putativeserotonergic psychedelic of thephenethylamine,2C, and25-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 like25CN-NBOH,DMBMPP, andLPH-5.[1] The drug produces psychedelic-like effects in rodents and hence may behallucinogenic in humans.[1] TGF-8027 was first described in the literature in 2025.[1]
TGF-8027 acts as a highlyselectiveserotonin5-HT2A receptorfull agonist.[1] Itsaffinities (Ki) were 7.4nM at the serotonin 5-HT2A receptor, 390nM at the serotonin5-HT2B receptor, and 1,100nM at the serotonin5-HT2C receptor.[1] The drug'sEC50Tooltip half-maximal effective concentration andEmaxTooltip maximal efficacy values in terms ofGq dissociation were 3.3nM (91%) at the human serotonin 5-HT2A receptor, 7,600nM (45%) at the human serotonin 5-HT2B receptor, and 160nM (123%) at the human serotonin 5-HT2C receptor.[1] It was also assessed at these receptors with otherassays.[1] In addition, TGF-8027 was screened at a large panel of othertargets, includingreceptors andtransporters, and showed relatively littleaffinity 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 ofcalcium flux, and 2,450-fold selectivity in terms ofIP1 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 as25CN-NBOH,DMBMPP, andrac-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 thehead-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 aracemic mixture of (+)- and (–)-enantiomers, with the (–)-enantiomer being a morepotent 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]
TGF-8027, also known asN-[1-(2-hydroxyphenyl)ethyl]-2,5-dimethoxy-4-cyanophenethylamine, is asubstituted phenethylamine and a2C and25-NB (NBOH)derivative.[1] It is specifically the derivative of25CN-NBOH in which thebenzyl group has beenα-methylated.[1] The compound is aracemic mixture of (+)- and (–)-enantiomers.[1] A series of otheranalogues of TGF-8027 have also been reported, some of which show further improved serotonin 5-HT2A receptor selectivity relative to TGF-8027 itself.[1]
TGF-8027 was first described in thescientific literature by John McCorvy's lab and colleagues in 2025.[1] The group also includedAdam Halberstadt.[1] The serotonin 5-HT2A and 5-HT2C receptors show considerablehomology, which has made development of selective serotonin 5-HT2A receptor agonists difficult.[1] TGF-8027 was discovered via arationalstructure-guided design that took advantage of an identified single-residue difference between the serotonin 5-HT2A receptor and the serotonin 5-HT2C receptor intransmembrane 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 thehead-twitch response assay, because it showed among the highest selectivity andpotency at the mouse serotonin 5-HT2A receptor in addition to the human serotonin 5-HT2A receptor.[1]
