Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 467

aldosterone biosynthesis. In this model, the resultant elevation in circulating
aldosterone levels contributes salt and volume retention, adverse cardiac
remodeling, and heart failure progression. 55

3.3. The Screener s dilemma

Results such as these help validate the concept that biased ligands can be used
to produce biological effects not attainable through conventional agonism or
antagonism, but they also highlight a current barrier to the rational design of
arrestin pathway-selective drugs. It would not have been possible to predict
that in vivo , (D-Trp 12 ,Tyr 34 )-bPTH(7-34) would increase bone mass, or SII
would promote aldosterone biosynthesis and salt retention, based on our
prior knowledge of their in vitro efficacy profile or the in vivo mechanism
of action of the parent hormones.
Figure 18.2 illustrates the point. At each in vitro level for which at least
some data are available, arrestin-selective biased agonists activate a subset of
the pathways affected by the native agonist. Biophysical measurements of
receptor conformation are most consistent with the interpretation that
ligands stabilize different active receptor conformations in different propor-
tions. 34 Biased ligands may favor receptor conformations that normally rep-
resent a minor proportion of the conformational population produced by
the conventional agonist, but they are inevitably subject to the steric con-
straints imposed by receptor structure and are unlikely to couple the receptor
to novel non-native signaling processes. Direct measurements of biased
ligand effects on receptor-effector coupling, second messenger generation,
and cell behavior are consistent with the hypothesis that biased ligand effects
comprise a subset of those produced by the native ligand. Even global pro-
teomic approaches have thus far failed to find unique biology in the short
term signaling response to biased ligands. 41 In vivo , however, the available
data suggest that biased ligands can affect gene transcription and tissue phe-
notype in unpredictable ways, analogous to the “butterfly effect” of chaos
theory, where a small change at one place in a deterministic nonlinear system
can produce outputs so complex that the results mimic random behavior. 57
While it is clearly possible to characterize even subtle degrees of ligand
bias in vitro, 23,25 the “screener's dilemma” arises from not knowing what
information is necessary to adequately predict the in vivo efficacy of a poten-
tial biased therapeutic. Because efficacy is pluridimensional and ligands are
biased, drug discovery programs must at least consider the possibility of
unpredicted “on-target” effects, not “off-target” effects arising from

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