Thermodynamics of peptide and non-peptide interactions with the human 5HT1a receptor.

The human serotonin 1a receptor (H5HT1aR) is a highly studied member of the 7 transmembrane G protein-coupled receptors. This model receptor, negatively coupled to adenylyl cyclase via Gi, is linked to physiological processes such as cognition and mood regulation and to associated disorders like anxiety and depression. Gibb's free energies, enthalpies, and entropies were calculated for the agonist [(3)H]8-OH-DPAT in the presence of synthetic peptides derived from sequences of intracellular loops 2 and 3 of the H5HT1aR. For comparative purposes, the thermodynamic parameters were also determined in the presence of a limited number of ligand-binding site substances (the partial agonist dipropyltryptamine [DPT], and the full agonist [(3)H]8-OH-DPAT alone). All of these thermodynamic measurements were based on binding data accumulated over a range of temperatures (0-35 degrees C). Representative examples of binding constant experiments and van't Hoff plots are shown to establish the thermodynamic variables. Although differences exist between the peptides themselves and the non-peptide agonists, in all situations the binding events are highly entropy driven. Differences between this information and published data for rat 5HT1aR are discussed, as are relationships to other receptor systems. Overall, the conclusions should be useful in further defining a comprehensive model of 5HT1aR, and for future development of binding-site and non-binding-site directed agents for the receptor. Copyright 2010 S. Karger AG, Basel.