G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug
design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable,
due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of
the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined
high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among
GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically
distinct and less conserved binding sites, namely “allosteric” sites. Pursuing these sites
offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding
affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric
agonist and an allosteric modulator connected by a spacer and allowing binding with both the
orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype
selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and
provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review
the recent advances in the development of bitopic agonists/activators for various GPCR targets and their
novel therapeutic potentials.
Isothermal chemical denaturation to determine binding affinity of small molecules to G-protein coupled receptors
