RESUMEN
Naturally occurring psychedelics have been used for a long time as remedies or in religious ceremonies and recreational activities. Recent studies have proven the therapeutic potential of some psychedelic compounds to safely treat a wide range of diseases such as anxiety, depression, migraine, and addiction. It is hypothesized that psychedelic compounds like tryptamines can exert their effects by two possible mechanisms: binding to the transmembrane serotonin receptor and/or modifying the properties of the neuronal membrane that can alter the conformational equilibrium and desensitize receptors. The impact of three different tryptamine class compounds with a tertiary amine (dimethyltryptamine, bufotenine, and 5-MeO-DMT) in both neutral and charged forms on a model bilayer lipid membrane are studied using all-atom MD simulations. All compounds partition into the bilayer, and change membrane properties, but to different extents. We determine the tendency of compounds to partition into the membrane by free energy calculations. Neutral tryptamines partition into the bilayer almost completely. Dimethyltryptamine and 5-MeO-DMT cross the membrane spontaneously during the simulation time, but bufotenine does not, although it has the maximum effect on the structural properties of the membrane. However, protonated compounds partition partially into the bilayer and cannot pass through the middle of the membrane during the simulation time. In this way, subtle alteration of chemical structure can play a significant role in the improvement or deterioration of partitioning of these compounds into the bilayer and their passage across the membrane.
