Membrane Permeation of Psychedelic Compounds
ChemRxiv Vito Federico Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
The ability of classic psychedelics to permeate neuronal membranes and reach intracellular 5-HT2A receptors is critical for their therapeutic effects. Using molecular dynamics simulations, this computational study examined how structural modifications to tryptamines affect membrane permeability. Dimethylation of the primary amine group and adding a methoxy group at position 5 increased permeability. In contrast, substitutions at other positions on the indole ring and protonation of the molecules raised the energy barrier at the bilayer center, making the compounds highly impermeable. These findings can guide future drug design to develop psychedelics with enhanced activity.