G protein–coupled receptors (GPCRs) are an evolutionarily conserved family of signaling
molecules comprising approximately 2% of the human genome; this receptor family remains
a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of
drug action at GPCRs over the past decade have revealed existing and novel ligands that
exhibit polypharmacology—that is, drugs with activity at more than one receptor target for
which they were designed. These “off-target” drug actions can be a liability that causes …