Premium
Theoretical models for molecular mechanisms in biological systems: Tryptamine congeners acting on an LSD—Serotonin receptor
Author(s) -
Weinstein Harel,
Osman Roman,
Edwards W. Daniel,
Green Jack P.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560140742
Subject(s) - tryptamine , chemistry , molecule , reactivity (psychology) , partial charge , 5 ht receptor , polarization (electrochemistry) , electron affinity (data page) , density functional theory , computational chemistry , redistribution (election) , stereochemistry , serotonin , receptor , organic chemistry , medicine , biochemistry , alternative medicine , pathology , politics , political science , law
Molecular reactivity criteria obtained for a congeneric series of tryptamine derivatives have led to the following hypothesis for the interaction of these molecules with an experimentally defined LSD‐serotonin high‐affinity binding site: the difference between the affinity of 5‐hydroxytryptamine (5‐HT) and that of any other congener is related to the discrepancy between the preferred electrostatic orientation of 5‐HT and that of the congener in the field of the receptor. Ab initio LCAO‐SCF calculations of complexes between 5‐HT, 6‐HT, 5‐hydroxyindole (5‐HIND), and 6‐HIND with imidazolium cation, were used to test this hypothesis. For the particular configurations of the complexes presented here, the results indicate that the electrostatic orientation vectors determined from the reactivity characteristics of the molecules are good predictors of the preferred mutual orientations of the molecules in these complexes. The decomposition of the stabilization energies into electrostatic (ES), polarization (PL), exchange repulsion (EX), and “charge‐transfer” (CT + mix) terms provide the basis for the possible validity of the reactivity criteria by indicating that the complexes are electrostatic in nature. The small contribution of the (CT + mix) term indicates that the main changes in electron distribution upon complex formation are in the form of charge polarization. Density‐difference maps and partial integrations (in chosen planes) of the total electron density support this conclusion. These maps also indicate that the same pattern of charge redistribution is observed with all the tryptamine congeners studied, if the configuration of the complex is electrostatically equivalent to that formed between 5‐HT and the common receptor site. This is in full agreement with the biological data that show that all tryptamine congeners we study here have the same intrinsic activity. The polarization complexes with imidazolium are therefore considered a useful model for further studies of the molecular mechanisms in the interaction with the LSD‐serotonin binding site.