PMID- 38324395
OWN - NLM
STAT- Publisher
LR  - 20240224
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 63
IP  - 4
DP  - 2024 Feb 7
TI  - Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations.
PG  - 419-28
LID - 10.1021/acs.biochem.3c00598 [doi]
AB  - 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(2A)Rs), 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(2A)Rs. 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.
FAU - Palmisano, Vito F
AU  - Palmisano VF
AD  - Department of Chemistry, Universidad Autonoma de Madrid, Madrid 28049, Spain.
AD  - Theoretical Chemistry Group, Zernike Institute for Advanced Materials, University 
      of Groningen, Groningen 9747 AG, The Netherlands.
FAU - Agnorelli, Claudio
AU  - Agnorelli C
AD  - Center for Psychedelic Research, Division of Psychiatry, Department of Brain 
      Science, Imperial College of London, London SW7 2BX, U.K.
AD  - Unit of Psychiatry, Department of Molecular Medicine, University of Siena, Siena 
      53100, Italy.
FAU - Fagiolini, Andrea
AU  - Fagiolini A
AD  - Unit of Psychiatry, Department of Molecular Medicine, University of Siena, Siena 
      53100, Italy.
FAU - Erritzoe, David
AU  - Erritzoe D
AD  - Center for Psychedelic Research, Division of Psychiatry, Department of Brain 
      Science, Imperial College of London, London SW7 2BX, U.K.
FAU - Nutt, David
AU  - Nutt D
AD  - Center for Psychedelic Research, Division of Psychiatry, Department of Brain 
      Science, Imperial College of London, London SW7 2BX, U.K.
FAU - Faraji, Shirin
AU  - Faraji S
AD  - Theoretical Chemistry Group, Zernike Institute for Advanced Materials, University 
      of Groningen, Groningen 9747 AG, The Netherlands.
FAU - Nogueira, Juan J
AU  - Nogueira JJ
AUID- ORCID: 0000-0001-7419-5670
AD  - Department of Chemistry, Universidad Autonoma de Madrid, Madrid 28049, Spain.
AD  - IADCHEM, Institute for Advanced Research in Chemistry, Universidad Autonoma de 
      Madrid, Madrid 28049, Spain.
LA  - eng
PT  - Journal Article
DEP - 20240207
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
SB  - IM
PMC - PMC10882957
COIS- The authors declare no competing financial interest.
EDAT- 2024/02/07 18:42
MHDA- 2024/02/07 18:42
PMCR- 2024/02/22
CRDT- 2024/02/07 12:13
PHST- 2024/02/07 18:42 [pubmed]
PHST- 2024/02/07 18:42 [medline]
PHST- 2024/02/07 12:13 [entrez]
PHST- 2024/02/22 00:00 [pmc-release]
AID - 10.1021/acs.biochem.3c00598 [doi]
PST - aheadofprint
SO  - Biochemistry. 2024 Feb 7;63(4):419-28. doi: 10.1021/acs.biochem.3c00598.