  G protein-coupled receptors (GPCRs) constitute a large family of receptor
proteins that sense molecular signals on the exterior of a cell and activate
signal transduction pathways within the cell. Modeling how an agonist activates
such a receptor is fundamental for an understanding of a wide variety of
physiological processes and it is of tremendous value for pharmacology and drug
design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a
model for the mechanism by which olfactory GPCRs are activated by a bound
agonist. We apply this hypothesis to GPCRs within the mammalian nervous system
using quantum chemical modeling. We found that non-endogenous agonists of the
serotonin receptor share a particular IET spectral aspect both amongst each
other and with the serotonin molecule: a peak whose intensity scales with the
known agonist potencies. We propose an experiential validation of this model by
utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its
deuterated isotopologues; we also provide theoretical predictions for
comparison to experiment. If validated our theory may provide new avenues for
guided drug design and elevate methods of in silico potency/activity
prediction.
