posted on 2024-02-07, 16:06authored byVito F. Palmisano, Claudio Agnorelli, Andrea Fagiolini, David Erritzoe, David Nutt, Shirin Faraji, Juan J. Nogueira
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 (HT2ARs), 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-HT2ARs. 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.