Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 455

2. BIASED GPCR AGONISM
Classical receptor theory is grounded in the premise that GPCRs exist
in equilibrium between inactive and active conformations and that ligands
affect signaling by binding with variable degrees of selectivity to the inactive
(R) and active (R * ) receptor states. For “biased” agonsim to be possible,
there must be at least two distinct active receptor conformations that can
be distinguished functionally, that is, that couple differently to downstream
effectors. In this case, ligands could conceivably display selectivity for the
different active states, just as they can between the inactive and active states,
allowing the ligand to “bias” signaling.
2.1. Single and multiple active state models of GPCR signaling
When only a single readout of receptor activity is considered, the actions of a
drug or hormone can be adequately described by two terms: affinity, the
equilibrium dissociation constant of the ligand-receptor complex, and max-
imal system response, which is a function of efficacy. 12,13 In this context, it
is necessary to account for only two receptor conformations: an “off” state
(R) that is silent in the assay and an “on” state (R * ) that produces the
measured response. Early allosteric models of GPCR activation envisioned
that receptors exist in spontaneous equilibrium between unique R and R *
conformations, and that ligands possessing intrinsic efficacy act by perturbing
this equilibrium so as to increase or decrease the fraction of receptors in
the R * conformation. 14-16 Since, in most cases, spontaneous adoption of
the R * state is a rare event, orthosteric ligands that preferentially stabilized
R * were described as full or partial agonists depending on whether the
response at saturating ligand concentration reached the maximal system
response, while those that had no apparent efficacy but competitively
inhibited agonist effects were classified as antagonists.
The spectrum of ligand activity was broadened by the discovery of con-
stitutively activating GPCR mutations that generate measurable levels of
receptor activity in the absence of ligand, since they allowed antagonists
to be further divided into those that suppressed basal activity and those that
had no effect even in systems with a high basal tone. 17-19 Thus, in two-state
models, agonists are ligands that stabilize R * , pulling the equilibrium toward
the “on” state, “neutral” antagonists bind indiscriminately to R and R * , pro-
ducing no measurable response but blocking the action of agonists, and
inverse agonists are ligands that appear as antagonists when basal receptor