The potential for selective pharmacological therapies through biased receptor signaling

Abstract

The discovery that not all agonists uniformly activate cellular signaling pathways (biased signaling) has greatly changed the drug discovery process for agonists and the strategy for treatment of disease with agonists. Technological advances have enabled complex receptor behaviors to be viewed independently and through these assays, the bias for an agonist can be quantified. It is predicted that therapeutic phenotypes will be linked, through translational studies, to quantified scales of bias to guide medicinal chemists in the drug discovery process.

Figure 1

Effects of isoproterenol and pirbuterol on rat atrial isometric contraction peak height (inotropy; filled circles) and rate of relaxation (lusitropy; open circles). The concentration-response curve for lusitropy is shifted 3-fold to the left of the curve for inotropy indicating a difference in the intrinsic coupling efficiencies of the β-adrenoceptor to these two physiological processes. Data redrawn from [10].

Figure 2

Molecular mechanism for agonist-directed biased signaling. Agonist A stabilizes a conformation of the receptor that preferably activates pathway 1 while agonist B stabilizes a receptor conformation that preferably activates pathway 2.

Figure 3

Impact of agonist-directed stimulus on drug screening. Canonical strategies for high throughput (HTS) screening pass the most active molecules from the HTS (represented by the dextral tail of the Boltzman distribution representing the best responses in the HTS) into secondary assays and animal models for further testing. To detect bias in signaling, the active molecules from the HTS are all tested in another functional assay for another signaling pathway and the most active molecules from that assay pooled with the actives from the HTS for further testing. The most active molecules in the secondary biased assay often are not the most active in the HTS thus a spectrum of agonists of differing stimulus bias is tested in animal models.