Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations

Abstract

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT_2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT_2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity.

Figure 1

Model of the neuroplastic effects of classic psychedelics mediated by the intracellular 5-HT_2AR postsynaptic molecular pathway. Modifying the primary amine group of tryptamines through alkylation influences their ability to penetrate the neural membrane, with only N-methylated and N,N-dimethylated tryptamines capable of entering the intracellular space. These compounds then bind to a pool of intracellular 5-HT_2ARs, triggering different pathways that induce changes in the structure and function of neurons.

Figure 2

(A) Twelve molecules under investigation. (B) Licorice structure of a POPC lipid divided into its four main components: alkyl chain, glycerol, phosphate, and choline. Color code: C atoms are shown in cyan, hydrogen atoms in white, oxygen atoms in red, nitrogen atoms in blue, and phosphorus atoms in ochre.

Figure 3

(A) Representation of N,N-OME (green) in bulk water (cyan) and a POPC lipid bilayer (orange). (B) Computational protocol followed for all the ligands under investigation.

Figure 4

(A) Log P_eff vs the experimental dendritogenesis efficacy of the nine drugs studied in Vargas et al. R corresponds to the Pearson correlation coefficient and p corresponds to the statistical significance at α = 0.05. (B) Symmetric PMF of all the molecules under investigation.

Figure 5

(A) PMF for TRY, N-TRY, and N,N-TRY. Decomposition of the energy into van der Waals (ΔG_vdw), electrostatic (ΔG_el), and implicit generalized Born solvation, (ΔG_gb), in the (B) minima and (C) maxima of the compounds.

Figure 6

(A) PMF for N,N-OME, N,N-TRY, and N,N-SER. Decomposition of the energy into van der Waals (ΔG_vdw), electrostatic (ΔG_el), and implicit generalized Born solvation, (ΔG_gb), in the (B) minima and (C) maxima of the compounds.

Figure 7

(A) PMF for OME, TRY, and SER. Decomposition of the energy into van der Waals (ΔG_vdw), electrostatic (ΔG_el), and implicit generalized Born solvation, (ΔG_gb), in the (B) minima and (C) maxima of the compounds.

Figure 8

(A) PMF for PSI, N-PSI, N,N-PSI, SER, N-SER, and N,N-SER. Decomposition of the energy into van der Waals (ΔG_vdw), electrostatic (ΔG_el), and implicit generalized Born solvation, (ΔG_gb), in (B) minima and (C) maxima of the compounds.

Figure 9

(A) PMF for TRY, N,N-TRY, TRY⁺, and N,N-TRY⁺. Decomposition of the energy into van der Waals (ΔG_vdw), electrostatic (ΔG_el), and implicit generalized Born solvation, (ΔG_gb), in the (B) minima and (C) maxima of the compounds.