Tetrahydropyridinylpyrrolopyridine 5-HT2A partial agonists; (R)-3-(5-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine ((R)-69); CAS 2765652-48-8 ((R)-69); PC-49805 (ProbeChem catalog) · Evidence-based safety and harm-reduction overview.
| Also known as | Tetrahydropyridinylpyrrolopyridine 5-HT2A partial agonists; (R)-3-(5-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine ((R)-69); CAS 2765652-48-8 ((R)-69); PC-49805 (ProbeChem catalog) |
| Category | Research Chemical |
| Molecular formula ((R)-69) | C13H15N3, MW 213.28 g/mol |
| CAS number ((R)-69) | 2765652-48-8 |
| 5-HT2A EC50 | (R)-69: 41 nM; (R)-70: 110 nM (partial agonist) |
| Signaling bias | Gq/11-biased; low beta-arrestin2 recruitment - mechanistically distinct from psilocybin/LSD |
| Selectivity over 5-HT2C | (R)-69: 29-fold; (R)-70: 51-fold |
| Development stage | Preclinical only; academic origin (Roth Lab, UNC Chapel Hill); no IND, no clinical trials, no pharma partner disclosed |
| US legal status | Unscheduled research compounds in the United States. No FDA approval, no IND filing, no DEA Schedule classification identified as of mid-2026. These are unapproved investigational substances available commercially from chemical suppliers (e.g., ProbeChem at research scale) and are not approved, licensed, or cleared for human use or consumption. Regulatory status in other jurisdictions has not been characterized. |
(R)-69 and (R)-70 are a structurally related pair of small-molecule 5-HT2A serotonin receptor partial agonists built on a tetrahydropyridinylpyrrolopyridine scaffold. They were identified in 2022 through a computational ultra-large-library docking campaign against the 5-HT2A receptor and are notable for two properties: antidepressant-like activity in preclinical rodent models, and an apparent absence of the hallucinogenic behavioral signature associated with classical 5-HT2A agonists such as psilocybin or LSD. All data on these compounds are preclinical. No human trials have been conducted or registered.
Both compounds act as partial agonists at the 5-HT2A receptor with measurable selectivity over the closely related 5-HT2B and 5-HT2C subtypes. (R)-69 shows approximately 4.6-fold selectivity over 5-HT2B and 29-fold over 5-HT2C; (R)-70 shows approximately 6.4-fold over 5-HT2B and 51-fold over 5-HT2C. The mechanistically distinctive feature is signaling bias: both compounds preferentially activate Gq/11 protein-coupled signaling over beta-arrestin2 recruitment. Classical hallucinogenic 5-HT2A agonists (LSD, psilocybin metabolite psilocin) are generally characterized as arrestin-biased, and it is hypothesized - though not yet proven in humans - that Gq bias without arrestin engagement may account for the absence of hallucinogenic behavioral effects seen in rodents. Neither compound showed hERG channel antagonism or significant off-target GPCR activity in the reported screening panel.
Described for the first time in a 2022 Nature paper from the laboratory of Bryan L. Roth at the University of North Carolina at Chapel Hill (PMID 36171289). The compounds emerged from a bespoke computational docking campaign screening approximately 75 million synthesizable tetrahydropyridine structures against a cryo-EM structure of the 5-HT2A receptor. The study was motivated by interest in separating the antidepressant-relevant signaling of psychedelic compounds from their hallucinogenic properties. The authors explicitly noted that the compounds required further optimization before being considered drug candidates, and no pharmaceutical development partnership has been publicly reported as of July 2026.
All existing evidence is preclinical (rodent models). In mouse tail-suspension tests - a standard antidepressant screen - both compounds reduced immobility at doses of approximately 0.5-1 mg/kg, with effects reportedly persisting 24 hours post-dose. In a learned helplessness model, (R)-70 restored sucrose preference on day 0, a result the authors compared favorably to psilocin efficacy. The compounds blocked LSD-induced head-twitch response (HTR) in mice, consistent with competitive antagonism at 5-HT2A, and neither compound produced HTR or prepulse inhibition disruption on its own. No conditioned place preference, locomotor stimulation, or behavioral sensitization was observed. Brain penetration was reported as favorable relative to classical psychedelics. No human pharmacokinetic, pharmacodynamic, or safety data exist. Long-term toxicity, human dosing, abuse liability in humans, effects on neuroinflammation, glutamate signaling, and dendritic spine density remain entirely uncharacterized.
Literature doses in rodent studies ranged from approximately 0.5 to 1 mg/kg (intraperitoneal or similar routes in mice). These figures cannot be extrapolated to human doses using simple weight-based conversion; interspecies pharmacokinetic differences, route of administration, and human receptor pharmacology would all need to be independently established in clinical trials. No human dosing information exists. This entry does not constitute a dosing recommendation or protocol. Consult a licensed clinician before considering any investigational compound.
This is general research/context information, not medical advice or a recommended protocol.
No stacking or combination data exist for these compounds in any context. The receptor pharmacology raises theoretical concerns about additive or antagonistic effects with other serotonergic compounds. No evidence base supports combining these research chemicals with other agents.
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Get tested with Ulta Lab Tests →The key mechanistic distinction proposed in the Roth 2022 Nature paper is signaling bias. Classical hallucinogens like LSD and psilocybin's active metabolite are associated with beta-arrestin2 recruitment at 5-HT2A, while (R)-69 and (R)-70 preferentially activate Gq/11 signaling with minimal arrestin engagement. In mice, neither compound produced the head-twitch response - the standard rodent behavioral proxy for hallucinogenic activity - whereas LSD-induced HTR was blocked by these compounds, consistent with competitive 5-HT2A occupancy. Whether this translates to a non-hallucinogenic profile in humans is entirely unknown; no human data exist.
No. All antidepressant efficacy data are from rodent models (tail-suspension test, learned helplessness, sucrose preference assays). No clinical trials in humans have been conducted or registered. Extrapolating rodent behavioral outcomes to human therapeutic benefit is speculative, particularly for compounds at this early a stage of development.
As of July 2026, (R)-69 and (R)-70 are not scheduled by the DEA, not approved by the FDA, and have no IND (Investigational New Drug) application on record. They exist as unclassified research chemicals. Their unscheduled status does not make them legal for human use - unapproved drugs cannot lawfully be administered to humans outside of an authorized clinical trial.
No dosing recommendation can be provided. No human pharmacokinetic or pharmacodynamic data exist, no safe or effective human dose has been established, and these compounds are not approved for human use. Rodent study doses (0.5-1 mg/kg IP in mice) cannot be meaningfully converted to human equivalents without clinical data. Anyone considering investigational compounds for a medical condition should consult a licensed clinician.
They emerged from a computational docking campaign described in a 2022 Nature paper from Bryan Roth's laboratory at UNC Chapel Hill. The team virtually screened approximately 75 million synthesizable tetrahydropyridine structures against a 5-HT2A receptor structure and synthesized high-scoring hits. (R)-69 and (R)-70 were among the leads selected for in vitro and in vivo characterization.
No pharmaceutical development partnership or IND filing has been publicly reported as of July 2026. The Roth 2022 paper itself stated the compounds 'demand more exploration and optimization before they can be considered drug candidates.' They remain academic research tools at this time.
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