LPH-5 (drug)

LPH-5
Clinical data
Other names(S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine; (S)-2C-TFM-3PIP; (S)-β,N-Trimethylene-2C-TFM
Drug classSelective serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen; Antidepressant
ATC code
  • None
Legal status
Legal status
  • In general unscheduled
Identifiers
  • (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC14H18F3NO2
Molar mass289.298 g·mol−1
3D model (JSmol)
  • COC1=CC([C@@]2([H])CNCCC2)=C(OC)C=C1C(F)(F)F
  • InChI=InChI=1S/C14H18F3NO2/c1-19-12-7-11(14(15,16)17)13(20-2)6-10(12)9-4-3-5-18-8-9/h6-7,9,18H,3-5,8H2,1-2H3/t9-/m1/s1
  • Key:NZKYTYHIERLZBG-SECBINFHSA-N

LPH-5, also known as (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine or as (S)-2C-TFM-3PIP, is a psychedelic drug of the phenethylamine, 2C, and 3-phenylpiperidine families which is under development for potential medical use.[1][2][3][4][5] It is a cyclized phenethylamine and is the derivative of 2C-TFM in which the β position has been connected to the amine to form a piperidine ring.[1][2][3]

Interactions

See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

Pharmacodynamics

LPH-5 acts as a potent partial agonist of the serotonin 5-HT2A receptor (Ki = 1.3 nM, EC50Tooltip half-maximal effective concentration = 2.1–25 nM, EmaxTooltip maximal efficacy = 56–94%).[3][6] It shows 10- to 100-fold selectivity for the 5-HT2A receptor over the serotonin 5-HT2B and 5-HT2C receptors in terms of affinity and activational potency.[3] Along with related compounds like 25CN-NBOH, DMBMPP, and TGF-8027, LPH-5 is said to be one of the few truly selective serotonin 5-HT2A receptor agonists.[1][2][3][7]

The drug robustly induces the head-twitch response as well as persistent and robust antidepressant-like effects in rodents.[3] Owing to its high selectivity for the serotonin 5-HT2A receptor, LPH-5 is expected to avoid the cardiac and other risks of serotonin 5-HT2B receptor activation.[8]

Chemistry

Analogues

LPH-5's analogue LPH-48 is likewise a selective serotonin 5-HT2A receptor agonist and psychedelic with similar characteristics.[9][10] However, this drug has a shorter duration of action than LPH-5.[10] As with LPH-5, LPH-48 is also under development by Lophora for potential medical use.[9][10]

History

LPH-5 was patented in 2021[6] and was first described in the scientific literature by Emil Märcher-Rørsted and colleagues in 2024.[2] These researchers are affiliated with the Danish pharmaceutical company Lophora.[2] In late 2025, LPH-5 was suggested as a possible alternative and replacement of DOI for use in scientific research.[11]

Research

LPH-5 is under development by Lophora and Atai Beckley (formerly Atai Life Sciences and Beckley Psytech) for the potential treatment of major depressive disorder.[4][5] As of May 2025, it is in phase I clinical trials for this indication.[4][5][12][13][14]

See also

References

  1. ^ a b c Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". British Journal of Pharmacology bph.17361. doi:10.1111/bph.17361. PMID 39354889.
  2. ^ a b c d e M Ro Rsted E, Jensen AA, Smits G, Frydenvang K, Kristensen JL (May 2024). "Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists". Journal of Medicinal Chemistry. 67 (9): 7224–7244. doi:10.1021/acs.jmedchem.4c00082. PMC 11089506. PMID 38648420.
  3. ^ a b c d e f Jensen AA, Cecchi CR, Hibicke M, Bach AH, Kaadt E, Märcher-Rørsted E, et al. (June 2025). "The Selective Serotonin 5‑HT2A Receptor Agonist (S)‑3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents". ACS Pharmacology & Translational Science. 8 (6): 1791–1803. doi:10.1021/acsptsci.5c00208. PMC 12171885. PMID 40534669.
  4. ^ a b c "LPH 5". AdisInsight. 11 November 2025. Retrieved 1 December 2025.
  5. ^ a b c "Delving into the Latest Updates on LPH-5 with Synapse". Synapse. 15 November 2025. Retrieved 1 December 2025.
  6. ^ a b US 2021/0137908, Kristensen JL, Jensen AA, Märcher-Rørsted E, "5-HT2A Agonists for Use in Treatment of Depression.", published 13 May 2021, assigned to Lophora ApS. 
  7. ^ Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, et al. (October 2025). "Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design". Journal of Medicinal Chemistry. 68 (19) acs.jmedchem.5c01855. doi:10.1021/acs.jmedchem.5c01855. PMID 40997862.
  8. ^ Peplow M (June 2024). "Next-generation psychedelics: should new agents skip the trip?". Nature Biotechnology. 42 (6): 827–830. doi:10.1038/s41587-024-02285-1. PMID 38831049. Another problem is that some classical psychedelics are also agonists of the 5-HT2B receptor, which is expressed in heart tissue and can cause long-term cardiac problems. Kristensen's company Lophora aims to solve that with its lead compound LPH-5, a phenylethylamine derivative with an extra molecular ring that makes it less flexible. LPH-5 has a 60-fold higher selectivity for 5-HT2A over 5-HT2B.
  9. ^ a b "LPH 48". AdisInsight. 22 May 2024. Retrieved 30 October 2024. LPH 48 is a ligand therapeutic which has a similar pharmacological profile as psilocybin with superior selectivity and shorter duration, being developed by [...]
  10. ^ a b c Lophora (31 May 2024). "Lophora Submits Clinical Trial Authorisation (CTA) Application to the French Medicines Agency (ANSM) for Lead CNS Drug LPH-5" (PDF). Retrieved 30 October 2024. About LPH-48: LPH-48 is a shorter acting direct analog of LPH-5 with similar optimized characteristics and safety profile, but with a shorter duration of action. LPH-48 is designed as a fast-follower that shows significantly faster metabolism, indicating a shorter duration of action in man. LPH-48 is a representative of the same proprietary compound class as LPH-5 and is therefore endowed with the same optimized characteristics including favorable drug-like properties and a safe pharmacological profile.
  11. ^ Cameron LP, Jaster AM, Ramos R, Ullman EZ (2025). "The Utility of DOI For the Study of Serotonin 2A and 2C Receptors". Molecular Pharmacology 100093. doi:10.1016/j.molpha.2025.100093. Retrieved 1 December 2025.
  12. ^ "2025 Annual Meeting American College of Clinical Pharmacology®". Clinical Pharmacology in Drug Development. 14 (S1): 1–140. September 2025. doi:10.1002/cpdd.1588. PMID 40913464.
  13. ^ Clinical trial number NCT06722820 for "Study to Evaluate LPH-5 in Healthy Subjects" at ClinicalTrials.gov
  14. ^ Tandrup B (28 May 2025). "Lophora Announces First Subjects Dosed in Phase 1 Clinical Trial of LPH-5 – Lophora". Lophora –. Retrieved 1 December 2025.
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