David Lankri is an Associate Research Scientist at Columbia University, where his work merges synthetic chemistry and neuropharmacology to uncover novel therapeutics for the treatment of neuropsychiatric disorders. Before pursuing his Ph.D., he completed a B. Pharm in Drug Science, graduating magna cum laude, and an M.Sc. in Medicinal Chemistry through the excellence program at The Hebrew University of Jerusalem. His early research focused on developing methodologies for constructing complex organic frameworks, which became the cornerstone of his scientific career.
He earned his Ph.D. in Medicinal Chemistry at The Hebrew University of Jerusalem under the supervision of Prof. Dmitry Tsvelikhovsky, where he specialized in designing advanced synthetic strategies for the preparation of biologically relevant molecules. Under the mentorship of Prof. Dalibor Sames at Columbia University, Dr. Lankri investigates the pharmacology of psychoactive substances, with a particular emphasis on understanding how these molecules interact with neural pathways and receptor systems. His research encompasses the synthesis of novel alkaloids to the study of both psychedelic and other psychoactive compounds. His findings, recently published in Nature and ACS Chemical Neuroscience, have advanced the understanding of receptor signaling and highlighted the therapeutic potential of these compounds.

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Structural Insights into the Psychoactivity of Tryptamines: Conformational Analysis, Permeability, and MAO Metabolism

Psilocin (4-OH-DMT) is a potent, orally active psychedelic tryptamine that can be psychoactive at doses as low as 3 mg. In contrast, its regioisomer bufotenine (5-OH-DMT) is reportedly non-psychoactive at oral doses up to 100 mg, despite being a stronger 5HT2A receptor agonist in vitro. Differential degradation by MAO-A and MAO-B is typically considered as the main factor contributing to the oral activity differences, but no studies have directly compared enzymatic activity across DMT, psilocin, bufotenine, and related tryptamines. Bufotenine's lack of psychoactivity has also been attributed to limited blood-brain barrier (BBB) penetration, based on logP studies, although no direct evidence supports this explanation. Psilocin’s ability to mask polar groups by forming an intramolecular hydrogen bond (pseudo-ring conformation) in apolar media may enhance membrane partitioning which could explain the logP differences. However, the impact of this conformation in polar environments remains underexplored.
Inspired by previous work, we performed NMR conformational analysis on twelve substituted tryptamines in various solvents. Most showed a preference for trans conformers, except the 4-OH substituted tryptamines, which favored an eclipsed conformation in nonpolar media, consistent with the previously described formation of an intramolecular hydrogen bond. Interestingly, in methanol and water, the trans conformer was less dominant, with the gauche conformer stabilized by intramolecular interactions. Significant indole ring deuteration was observed in deuterated methanol and water, indicating an intramolecular acid-base reaction between the amino and phenol groups. NMR diffusion studies showed that psilocin has diffusion properties similar to DMT, while bufotenine diffuses more slowly.
These findings suggest that 4-OH tryptamines engage in intramolecular interactions even in polar environments, which may explain differences in pKa values, diffusion, and partitioning properties. We will present results from the MDCK/MDR1 permeability assay on N,N-methylethyltryptamine (MET), 4-OH-MET, and 5-OH-MET to assess BBB penetration, alongside MAO-A and MAO-B enzymatic profiles for DMT, bufotenine, psilocin, and other hydroxy-DMT analogs.