Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations

Introduction

Palmisano and colleagues situate this work within the recent revival of interest in classic psychedelics, which are structurally related to serotonin (5-HT) and act as agonists at the 5-HT2A receptor. Previous pharmacological and animal research links 5-HT2A agonism to rapid neurophysiological and neuroplastic changes that may underlie therapeutic effects in conditions such as depression and anxiety. However, there is mechanistic uncertainty regarding why closely related 5-HT2A agonists differ in their neuroplastic and subjective effects. Recent evidence suggests that activation of intracellular pools of 5-HT2A receptors — requiring a compound to cross the neuronal plasma membrane — may be a key determinant of these differences, and that lipophilicity correlates with neuroplasticity-promoting properties in earlier studies. This study aims to characterise, by molecular simulation, how structural modifications to tryptamine derivatives influence their ability to permeate a model lipid bilayer and thereby access intracellular receptor pools. The investigators selected 12 tryptamines (tryptamine, serotonin, 5-methoxy-tryptamine, 4-hydroxy-tryptamine and their N-methyl and N,N-dimethyl analogues) and used classical molecular dynamics (MD) with umbrella sampling (US) to compute potentials of mean force (PMFs), local diffusivity, and effective permeability coefficients (log Peff). The intent was to isolate the effects of N‑alkylation, indole-ring substitution and substitution position, and protonation state on membrane permeation, with an eye toward informing rational design of psychedelics with altered intracellular access.